GLP-1 agonists and the kidney

GLP-1 has a short half-life and is actively excreted by the kidneys. GLP-1 receptor agonists have a prolonged half life in the circulation and are passively excreted by the kidney. GLP-1 itself interacts with receptors in the renal vasculature and in the proximal tubule. The latter is functionally linked to the Na+ /H+ exchanger isoform 3 (NHE3) transporter, a membrane pump that retrieves sodium and other electrolytes from the tubular fluid. Since GLP-1 agonists are filtered by the kidney, concentrations increase in the presence of renal insufficiency. This has the potential to creat a vicious circle in which agonist therapy induces vomiting and dehydration, especially when other predisposing factors (e.g. drugs) are present. The salt-wasting action of GLP-1 receptor stimulation may restrict the ability of the kidney to resist this challenge. Most cases appear to resolve if appropriate action is taken and the drug withdrawn, but irreversible damage resulting in a need for dialysis or transplantation has been reported. Reported cases of renal failure have usually been due to severe dehydration with resultant ischaemic damage to the kidney, but a minority of cases appear to develop renal injury in the absence of dehydration, and this phenomenon is not well understood.

Background

Exenatide exerts its effects by binding to the GLP-1 receptor, which is present on the surface of many cells, and the consequences of this binding may produce changes unrelated to its more useful pharmacologic actions. In the kidney, the GLP-1 receptor is present in cells lining blood vessels and in the proximal renal tubule, which plays a role in regulating the composition of the urine. Stimulation of the receptor in blood vessels results in relaxation of smooth muscle and increased renal blood flow. Stimulation of the receptor in the proximal tubule results in increased loss of salt, water and electrolytes in the urine. In health, these effects may be mildly beneficial, but they might also potentially reduce the ability of the kidney to limit fluid loss under conditions of dehydration and stress.

EMA (European Medicines Agency) noted as early as December 2007 that there had been “rare, spontaneously reported events of altered renal function [with exenatide], including increased serum creatinine, renal impairment, worsening chronic renal failure and acute renal failure sometimes requiring hemodialysis”[1]. FDA requested revisions to the label in 2009[2]. Physicians were advised not to use exenatide in patients with severe renal impairment, and to exercise caution in those with lesser degrees of renal impairment. Several case reports have been described in the literature.

Renal problems experienced with exenatide appear to fall into two main categories. In the first category, exposure to exenatide has been associated with dehydration because of prolonged vomiting and/or diarrhea; the second (much rarer) category includes patients in whom renal impairment has developed in the absence of severe dehydration. Acute pancreatitis has been reported in association with GLP-1 based therapies, and is itself a well-established cause of acute renal failure, but does not appear to have been a factor in the cases described. Dehydration from whatever cause may, if sufficiently severe, result in acute renal failure. This will be more likely to occur if kidney function is already compromised by increasing age, diabetes-related or other renal disease, concurrent illness or medication.

Use of a GLP-1 agonist may not only initiate dehydration, but may also exacerbate it. This is because GLP agonists are excreted via the kidneys, and the drug will accumulate in the circulation if kidney function is compromised, thus potentially worsening the vomiting and dehydration. A further potential factor is that exposure to exenatide increases salt and water loss in the urine, thus potentially limiting the ability of the kidneys to respond to dehydration by conservation of body fluids. Acute renal failure may be reversible, but may also result in chronic loss of renal function or renal failure requiring dialysis or transplantation.

Pharmacokinetic considerations

Exenatide has a half-life of ~1.5 hours following injection, and (since it is resistant to breakdown in the bloodstream) is excreted almost exclusively via the kidneys. The kidney is thus exposed to exceptionally high levels of this agent. The rate at which exenatide enters the urine is directly related to the filtering capacity of the kidney. This means that a healthy kidney can remove the drug from the circulation more effectively than a kidney that filters less effectively because of increasing age or a disease such as diabetes. Renal dysfunction prolongs the circulating half-life of exenatide and thereby raises the concentration of the drug to which the body is exposed.

Physiological Considerations

Exenatide has two distinct biologic effects upon renal function. It has diuretic and natriuretic actions (i.e. increases the loss of sodium, other electrolytes and water by the kidney), and it increases renal blood flow. These effects are mediated by the interaction between exenatide and GLP-1 receptors, which are present both in the proximal tubular cells of the kidney and in the renal vasculature.

The mechanisms underlying these actions are now reasonably well understood. The GLP-1 receptor is situated in the proximal convoluted tubule (PCT) of the kidney, and is functionally linked to the Na+ /H+ exchanger isoform 3 (NHE3) transporter, a membrane pump that retrieves sodium and other electrolytes from the tubular fluid (and thus from the urine), thereby returning them into the circulation. Activation of the GLP-1 receptor following binding to exenatide results in inactivation of this membrane pump, which leads to increased sodium loss in the urine. Sodium loss has osmotic effects which increase the volume of fluid lost in the urine. Exenatide is also a vascular relaxant, and increases the blood flow in the kidneys by mechanisms presumed to be similar to those demonstrated in other vascular beds.

The net effect of treatment therefore resembles that of a mild diuretic, and is potentially a useful property of the agent in some categories of patient, e.g. those with a raised blood pressure. These same properties do have the potential to exacerbate problems when the body is seeking to conserve fluid, as for example following dehydration.

Clinical Aspects

Exenatide has the potential to cause worsening renal function or acute renal failure by:

(1) Inducing severe vomiting and fluid loss, resulting in reduced renal perfusion, especially (but not exclusively) in those who already have compromised renal function. Compromised renal function is common in the diabetic population, due to the combination of age and disease.

(2) Impaired renal function, whether pre-existing or induced by acute dehydration, will reduce renal excretion of exenatide, causing plasma concentrations to rise in parallel with the loss of renal function. Increased concentrations of exenatide have the potential to aggravate nausea and vomiting.

(3) The additional effect of exenatide is to bind to GLP-1 receptors in the proximal tubule, with consequent partial inactivation of NHE3, a major sodium pumping mechanism. The effect of this will be to inactivate an important compensatory mechanism for acute dehydration and to increase the loss of salt and water from the body, potentially (and especially if the agent is not discontinued) creating a vicious cycle of fluid loss, dehydration and declining renal function. This phenomenon will be aggravated when exenatide is co-administered with other agents that promote sodium loss or have other renal effects, including diuretics and ACE inhibitors.

Case reports

Weise et al (2009) reported 4 patients with deteriorating renal function following treatment with exenatide. All had experienced nausea and vomiting. There was evidence of permanent loss of renal function in 3 patients. A renal biopsy in one patient showed ischemic glomeruli with severe interstitial fibrosis and early diabetic nephropathy[3] Bhatti et al (2010) reported 2 further patients. In one case renal dysfunction was associated with dehydration and responded to fluid therapy. In the other, there was no clinical evidence of dehydration. The patient had hematuria and proteinuria, and interstitial nephritis was suspected; partial recovery of renal function was seen following treatment with prednisolone. No renal biopsy was performed. López-Ruiz et al (2010) described a 20 year old man with type 2 diabetes in whom exenatide was substituted for insulin glargine. He was also taking diuretics and an angiotensin II receptor antagonist. Two months later he experienced severe dehydration culminating in ischemic renal failure. Recovery followed withdrawal of exenatide and the angiotensin II receptor antagonist[4].
Nandakoban et al (2013) reported a 58-year old man treated with metform and gliclazide who was prescribed exenatide 5 mcg bid. He had chronic renal impairment with serum creatinine concentration of 120 umol/l, and was on treatment with diuretics and candesartan (an angiotensin II receptor antagonist). His renal function, previously stable, declined over 2 months following exposure to exenatide, in the absence of dehydration. GFR fell from 59 to 39 ml min over 2 months. Exenatide was stopped, but renal function continued to deteriorate and GFR fell further to 16 ml min. Renal biopsy showed acute tubulointerstitial nephritis which responded partially but incompletely to treatment with prednisolone. This was considered by the authors to be the first report of biopsy proven acute tubulointerstitial nephritis, a condition associated with other types of drug therapy, in a patient on exenatide[5]. Kaakeh et al 2012 reported renal injury in association with liraglutide. In this instance, a 53 year-old woman presented with vomiting and severe dehydration one month after starting liraglutide, and renal biopsy showed evidence of acute tubular necrosis, consistent with the response to severe acute dehydration[6].

Summary

Exenatide, and potentially also liraglutide, have the potential to cause renal problems. In most cases this is due to acute dehydration superimposed upon chronic renal insufficiency or other predisposing factors, such as ACE inhibitors. The problem is generally self-limiting provided the agonist is withdrawn, but ischaemic damage may supervene and result in lasting damage. The manufacturers advise that these agents should not be used in those with chronic renal impairment.

A minority of case reports suggest renal damage in the absence of acute dehydration, and there is one report of tubulointerstitial nephritis, a rare drug-associated cause of kidney damage.

References

  1. ^ http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002020/WC500108239.pdf

  2. ^ http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm188703.htm

  3. ^ Weise et al. Exenatide-associated ischemic renal failure. Diabetes Care 2009;32:e22-3. doi: 10.2337/dc08-1309.

  4. ^ Lopez-Ruiz A et al. Acute renal failure when exenatide is co-administered with diuretics and angiotensin II blockers. Pharm World Sci 2010;32:559-61

  5. ^ Nandakoban H et al. Acute tubulointerstitial nephritis following treatment with exenatide. Diabet Med 2013;30:123-5

  6. ^ Kaakeh Y et al. Liraglutide-induced acute kidney injury. Pharmacotherapy 2012;32:e7-11. doi: 10.1002/PHAR.1014.

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