exenatide and Acute-Kidney-Injury

Topics: Acute Kidney Injury; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Middle Aged

Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury, particularly in diabetic patients. Previous studies have shown renoprotective effects of glucagon-like peptide-1 (GLP-1) signalling; however, its role in CIN remains unexplored. This study investigates the prophylactic effect of exendin-4, a GLP-1R agonist, against CIN in a rat model mimicking both healthy and diabetic conditions. Animals were randomly divided into 7 groups: a control sham group (n = 8), and 2 identical sets of 3 disease groups, one received exendin-4 before exposure to contrast medium (CM), while the other served as untreated control. The 3 disease groups represented diabetes (n = 8), CIN (n = 8), or diabetes and CIN combined (n = 8). Untreated groups showed deteriorating renal function as indicated by significantly higher levels of serum creatinine and blood urea nitrogen, malondialdehyde, and endothelin-1 and caspase-3 expression compared to the sham control group. This was accompanied by a significant decrease in tissue reserves of reduced glutathione, superoxide dismutase, nitrate and endothelin nitric oxide synthase as well as deteriorating renal histology. The CM-induced changes in diabetic rats indicate impaired renal function, oxidative stress, vascular dysfunction, and apoptosis, and were significance higher in intensity compared to non-diabetic rats. Pretreatment with exendin-4 ameliorated all the aforementioned CM-induced nephropathic effects independent of the glycemic state. To our knowledge, this is the first study describing the prophylactic renoprotective effects of exendin-4 against CIN. With the current pharmaceutical use of exendin-4 as a hypoglycaemic agent, the GLP-1R agonist becomes an interesting candidate for human clinical trials on CIN prevention.

Topics: Acute Kidney Injury; Animals; Antioxidants; Apoptosis; Blood Glucose; Contrast Media; Diabetes Mellitus, Experimental; Exenatide; Glucagon-Like Peptide-1 Receptor; Hemodynamics; Kidney Function Tests; Male; Oxidative Stress; Rats, Sprague-Dawley; Streptozocin

Accumulating evidence of the beyond-glucose lowering effects of a gut-released hormone, glucagon-like peptide-1 (GLP-1), has been reported in the context of remote organ connections of the cardiovascular system. Specifically, GLP-1 appears to prevent apoptosis, and inhibition of dipeptidyl peptidase-4 (DPP-4), which cleaves GLP-1, is renoprotective in rodent ischemia-reperfusion injury models. Whether this renoprotection involves enhanced GLP-1 signaling is unclear, however, because DPP-4 cleaves other molecules as well. Thus, we investigated whether modulation of GLP-1 signaling attenuates cisplatin (CP)-induced AKI. Mice injected with 15 mg/kg CP had increased BUN and serum creatinine and CP caused remarkable pathologic renal injury, including tubular necrosis. Apoptosis was also detected in the tubular epithelial cells of CP-treated mice using immunoassays for single-stranded DNA and activated caspase-3. Treatment with a DPP-4 inhibitor, alogliptin (AG), significantly reduced CP-induced renal injury and reduced the renal mRNA expression ratios of Bax/Bcl-2 and Bim/Bcl-2. AG treatment increased the blood levels of GLP-1, but reversed the CP-induced increase in the levels of other DPP-4 substrates such as stromal cell-derived factor-1 and neuropeptide Y. Furthermore, the GLP-1 receptor agonist exendin-4 reduced CP-induced renal injury and apoptosis, and suppression of renal GLP-1 receptor expression in vivo by small interfering RNA reversed the renoprotective effects of AG. These data suggest that enhancing GLP-1 signaling ameliorates CP-induced AKI via antiapoptotic effects and that this gut-kidney axis could be a new therapeutic target in AKI.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Apoptosis; Cisplatin; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Peptides; Piperidines; Receptors, Glucagon; Reperfusion Injury; RNA, Small Interfering; Uracil; Venoms

Acute tubulointerstitial nephritis, a cause of acute kidney injury, is seen occasionally following treatment with medications such as antibiotics and non-steroidal anti-inflammatory drugs. To date, the development of biopsy-proven acute tubulointerstitial nephritis after treatment with exenatide has not been reported.. A 58-year-old man was prescribed exenatide for poorly controlled Type 2 diabetes mellitus. He subsequently developed deterioration in kidney function, with the estimated glomerular filtration rate declining from 59 to 39 ml min(-1) 1.73 m(-2) over 2 months. Despite cessation of exenatide, there was continued deterioration in estimated glomerular filtration rate to 16 ml min(-1) 1.73 m(-2). He underwent renal biopsy and the sections showed active diffuse tubulointerstitial nephritis with infiltration of eosinophils. He was treated with prednisolone over several months with incomplete recovery in kidney function.. Acute tubulointerstitial nephritis should be suspected if there is deterioration in kidney function in a patient treated with exenatide in the absence of other causes of acute kidney injury such as dehydration or hypotension.

Topics: Acute Kidney Injury; Diabetes Mellitus, Type 2; Exenatide; Glomerular Filtration Rate; Humans; Hypoglycemic Agents; Male; Middle Aged; Nephritis, Interstitial; Peptides; Venoms

This study evaluated whether the risk of acute renal failure (ARF) increases with exenatide and sitagliptin use.. A retrospective cohort study of a large medical and pharmacy claims database was performed. Data for 4 91 539 patients were analysed. Cox proportional hazard models were used to compare the risk of ARF between diabetic and non-diabetic subjects and between diabetic patients treated with exenatide, sitagliptin and control medications.. Adjusted Cox analyses showed diabetic subjects had a higher risk of ARF [HR 1.51, confidence interval (CI) 1.26-1.81, p < 0.001] than non-diabetic controls. Compared with diabetic controls, neither exenatide (HR 0.77, CI 0.42-1.41, p = 0.40) nor sitagliptin (HR 1.17, CI 0.82-1.65, p = 0.39) increased the risk of ARF.. Our study revealed an increased incidence of ARF in diabetic versus non-diabetic patients but no association between use of exenatide or sitagliptin and ARF. Because of the limitations of this observational analysis, we cannot exclude the possibility of a very small increased risk.

Topics: Acute Kidney Injury; Adolescent; Adult; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Labeling; Exenatide; Female; Humans; Incidence; Male; Middle Aged; Peptides; Proportional Hazards Models; Pyrazines; Retrospective Studies; Risk Assessment; Sitagliptin Phosphate; Triazoles; Venoms; Young Adult

Case (description) the patient is a 20 years old male smoker, who was diagnosed with type 2 diabetes mellitus in 2006. Due to the inadequate response to the previously established treatment, the pharmacotherapy was modified by introducing exenatide (up to 10 μg, twice daily) instead of insulin glargine, but maintaining the treatment with the diuretic and angiotensin II receptor antagonist drugs. Two months later, the patient exhibited a very important intolerance to exenatide (continuous nausea, vomiting, and dehydration), finally leading to ischemic acute renal failure. When the angiotensin II receptor antagonist and exenatide were suspended, a very rapid recovery of renal function was observed. Conclusion ischemic acute renal failure is supposed to be the consequence of the extracellular volume contraction caused by exenatide (the result of continuous nausea and vomiting). This adverse effect could be caused by the co-administration of diuretics and angiotensin II receptor antagonists.

Topics: Acute Kidney Injury; Angiotensin Receptor Antagonists; Diabetes Mellitus, Type 2; Diuretics; Drug Interactions; Drug Therapy, Combination; Exenatide; Humans; Hypoglycemic Agents; Male; Peptides; Venoms; Young Adult