Prescribing in AKI

No specific treatments improve the outcome of AKI, management focusing on treatment of any acute illness triggering AKI and stopping medication that may exacerbate the renal injury.  The most important drugs in this respect are ACEI/ARB, NSAID (including COX-2 inhibitors) and diuretics.  

It is important to recognise also drugs which may accumulate causing toxicity and which must therefore be stopped or avoided in AKI.  Treatment of infection is important given that sepsis is a frequent trigger.  Some antibiotics should be avoided in AKI and this has been discussed previously.  The most important drugs to consider stopping in AKI are some drugs used for treatment of diabetes.  Information on use in renal impairment is lacking for many drugs, product information sheets and guidelines often advising against use because of a lack of information rather than evidence confirming an adverse effect.  If there is evidence that a drug will accumulate in AKI and that this accumulation is likely to have adverse effects, this is highlighted here with the suggestion that it should be stopped in AKI.

Prescribing in AKI

ACEI/ARB, NSAID and Diuretics

ACEI/ARB, NSAIDs and diuretics are the most important drugs of relevance to AKI.  It is important to reiterate that in most instances these drugs are not directly injurious to the kidneys, acting to exacerbate kidney injury in the context of other primary insults, due to limitation of protective intraglomerular pressure autoregulation.  Numerous studies have identified prescription of ACEI/ARB as a significant independent risk factor for AKI.  Similarly, all NSAIDs, including selective COX-2 inhibitors, may cause AKI due to predictable effects on glomerular haemodynamics (56).  Finally, diuretics may exacerbate intravascular volume depletion, precipitating or exacerbating AKI.

These effects are additive and concomitant administration of ACEI/ARB and NSAID/COX-2 inhibitors (including over the counter medications) in patients at risk of AKI should be avoided.  Lapi et al (57) identified the combination of ACEI/ARB, NSAID and diuretics as being particularly associated with an increased risk of admission for AKI as a primary diagnosis.

ACEI and ARBs are clearly indicated in many patients who are also at risk of AKI (T2DM, cardiac failure, CKD).  With respect to prevention of progression of kidney disease, it is the reduction of glomerular perfusion pressure, which is injurious in AKI, that protects against progressive damage in chronic kidney disease. In CKD the kidney is in essence compensating for the reduced filtration capacity by increasing perfusion pressure in the remaining glomeruli.  However, this drives progressive kidney damage.  Use of ACEI/ARB prevents this over-compensation but also positions the patient closer to the ‘cliff edge’ of AKI.  Similarly, the benefits of diuretics are clear but many of these patients will also be at risk of AKI.  Prescription of these medications is thus clearly indicated, but increases the risk of AKI and optimal use therefore requires close monitoring for AKI.  Education of patients about ‘sick day rules’ for stopping these agents has been advised (58).

Learning Point
Patients in whom there is a clear indication for ACEI/ARB should not be deprived of these drugs because of concerns about AKI
Safe use of these drugs in patients with additional risk factors for AKI requires recognition of this risk and appropriate monitoring, in particular during any intercurrent illness

If a patient experiences an initial episode of AKI, this defines them as someone who is close to this ‘cliff edge’.  On recovery, in the absence of intercurrent illness, use of ACEI/ARB, diuretics or both may again be safe and the benefits of these drugs can be realised.  However, as above, the patient will also inevitably be at increased risk of further episodes of AKI.

In contrast, for many patients, exposure to the risk of AKI associated with NSAID and selective COX-2 inhibitors is not justified by their benefits, other options being available.

Insulin and oral hypoglycaemic agents in AKI

Prescribing of oral hypoglycaemic agents in renal failure has been reviewed (59).  Specific aspects of relevance to AKI will be discussed here.

Metformin

Metformin is of particular interest as it is the first line oral hypoglycaemic agent for most patients with T2DM (60, 61).  However, the risk of lactic acidosis causes concern for prescribers and, as AKI and CKD are common in T2DM, clear guidance is required with respect to use of metformin in patients with renal impairment and in patients who develop AKI.  

Metformin is not nephrotoxic, but 90% is excreted by the kidneys.  Thus, it does not cause AKI but metformin will accumulate in AKI.  A Cochrane review (62) and nested case control series (63) have demonstrated that lactic acidosis is extremely rare with 3-4 cases for every 100,000 person-years of metformin treatment.  These reports found a lower incidence of lactic acidosis in metformin treated patients than in patients treated with other oral hypoglycaemic agents.  Importantly, Salpeter (62) concluded that metformin use is only associated with lactic acidosis if there is an underlying precipitating condition.  However, AKI may be one such condition and thus care should be taken in patients at risk of AKI.

Recommendations for use of metformin in CKD are conflicting. Product literature states that it is contraindicated in CKD stage 3-5, but published series and reviews support its use, with care, down to an eGFR of 30 mL/min/1.73 m2 (64-66).  In keeping with this, NICE guidance (67) recommends that the dose of metformin should be reviewed if serum creatinine exceeds 130 µmol/L (eGFR <45 mL/min/1.73 m2) and metformin should be stopped if serum creatinine is >150 µmol/L or if eGFR is <30 mL/min/1.73m2.  Caution is recommended for those at risk of a sudden deterioration in kidney function and those at risk of eGFR falling below 45 mL/min/1.73 m2.  Successive joint ADA and EASD position statements have recognised the above evidence (60) acknowledging that NICE guidance is “less proscriptive” than US guidelines, stating that this stance appears “very reasonable” (68).

Thus, metformin should be stopped if AKI is diagnosed, but may be safely restarted on recovery in many patients if renal function returns to baseline.  However, if there is considered to be a significant risk of further episodes of AKI alternative hypoglycaemic agents may be preferable.

Prescribing in AKI 2

Insulin

The 2012 update of the KDOQI Diabetes Guideline gives guidance on use of insulin and OHA in diabetes (69).  Furthermore, Lubowsky (70) has reviewed the multiple effects of chronic kidney disease on glucose homeostasis.  There is both an increased risk of hyperglycaemia and of acute hypoglycaemia, with it being difficult to predict the balance of these effects in an individual patient.  The reduced clearance of insulin makes it important to be aware of the possible need to reduce insulin dose if kidney function deteriorates, but this should be guided by increased frequency of blood glucose monitoring as intercurrent illness may modify this.  Use of short acting insulins may be preferable.

Sulfonylureas

Sulfonylureas differ in the importance of renal clearance to overall drug clearance and the renal clearance of active metabolites.  First generation sulfonylureas (SU) should be avoided in CKD and stopped if a patient develops AKI on the background of normal kidney function.  Of the second generation SUs, gliclazide and glipizide are of note. Renal clearance accounts for only 4% of total clearance of gliclazide and no active metabolites accumulate in CKD (71).  Glipizide is 90% cleared by the liver to inactive metabolites and may therefore be safely used in CKD 5.  Gliclazide and glipizide can therefore be continued in AKI although increased frequency of monitoring is advisable.

Gliptins

Gliptins can be used in CKD, but as most are cleared by the kidneys, dose titration is needed and they will accumulate in AKI.  As their action is ‘insulin dependent’ normal glucose homeostasis will still ‘work’ and will limit the consequences of this accumulation but in general they should be stopped in AKI.  Linagliptin is of note as the only gliptin to be cleared by the liver, it therefore being safe to use in CKD stage 4 and 5, with no dose adjustment needed (72).  Although no specific advice is available this should make it safe to continue in AKI.

Glinides

Repaglinide is 100% metabolized by the liver and may be used without dose adjustment in CKD4/5 with no increased risk of hypoglycaemia.  Nateglinide is 85% metabolized by the liver with the remainder excreted unchanged in the urine with weakly active metabolites cleared also by the kidneys.  There is therefore an increased risk of hypoglycaemia with worsening renal function.  Thus, although the risk in CKD is small (69), careful dose titration is recommended in severe renal impairment (70) and it would therefore seem advisable to stop these agents in AKI.

Thiazolidinediones

Thiazolidinediones are cleared by the liver and can be used in CKD (70).  However, other considerations, in particular fluid retention, may restrict their use in CKD and suggest it is advisable to stop in AKI.

GLP-1 agonists

Exenatide is metabolised by the kidneys and decreased clearance with significantly increased side effects are seen in CKD 4/5 (69). It should therefore be stopped in AKI.  The kidneys are not a major route of elimination of Liraglutide with plasma drug concentrations not affected by CKD 4/5 (69)  However, the manufacturer recommends avoidance in CKD =3 and it should therefore be stopped in AKI.

SGLT2 inhibitors

SGLT2 inhibitor lower blood glucose by reducing renal tubular glucose reabsorption thereby lowering plasma glucose. Despite the fact they are a class of drug that directly acts on the kidney they seem to have no role in the precipitation of AKI. There is emerging evidence that they have a beneficial effect on proteinuria and on the progression of CKD. They can be safely stopped short term in a patient with AKI.

Other agents 

Acarbose and miglitol are contraindicated in CKD 4/5 and they should therefore be stopped in AKI.

Pramlinitide is excreted by the kidneys, but has a wide therapeutic range and can be used in CKD.  It is not advised in CKD =4 and therefore should be stopped in AKI.

 


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