Common Medications Encountered in CKD:

A Focus on Proactive CKD Management

• Historically, focus of CKD was on renal replacement therapy: coordinating placement of vascular access, addressing uremic symptoms and complications, and providing dialysis.

• However, less than 2% of patients in CKD stages 2 and 3 and ~ 20% in stage 4 progress to end-stage renal disease (ESRD) and undergo dialysis.

• Due to varying rates of progression and competing risks for death such as cardiovascular disease, majority of CKD patients, particularly ≥ 75yo, die before reaching ESRD.

Bowel Cleansing Agents:

Which Ones Are Safe in CKD?

• Majority of CKD patients are in stages 2 and 3 vs. ESRD (HD or PD).
• In past decade, focus has shifted toward early diagnosis, treatment of underlying cause, and delaying progression of CKD rather than ESRD management alone.

BCMJ 2010;52(9):473-474.

Arch Intern Med. 2004;164:659–63

J Gen Intern Med. 2011 Apr; 26(4): 379–385.

Consider combination of lower volume PEG preparations (2L) with bisacodyl for those with stages 4 to 5 CKD (non-dialysis) to limit large fluid intake (4L).

* All bowel cleansing preparations require significant fluid intake and some may contain electrolytes including K+ (caution in CKD with hyperkalemia).

Delaying CKD Progression: Drug-Induced Acute Kidney Injury (AKI)

Gut. 2012 Nov;61(11):1525-32. Epub 2012 Jul 26.

Health Canada Drug Product Database

• Acute kidney injury (AKI) is a risk factor for the development of chronic kidney disease (CKD) and drugs account for ~20% of AKIs acquired in both community and hospital settings.

• According to data retrieved from the French National Pharmacovigilence Database (FPVD), approximately 15.2% of patients with drug-induced AKI require renal replacement therapy.

• The FPVD also found the following drug classes to be most commonly associated with AKI:

Metformin in Renal Impairment

• First-line antihyperglycemic agent in type II diabetes (T2DM) due to absence of weight gain and hypoglycemia, good tolerability, and affordability.

• Renally eliminated and contraindicated in eGFR <30ml/min due to concerns for lactic acidosis, which is associated with 50% mortality.

N Engl J Med 2014; 371:58-66.

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Br J Clin Pharmacol. 2016 Dec 21. doi: 10.1111/bcp.13216.

Risk for Lactic Acidosis

Metformin and IV Contrast

Renal Dose Adjustment

• Incidence of metformin-induced lactic acidosis (MALA) is rare: ~ 10 or less events per 100,000 patient-years of exposure.

• IV contrast used in contrast-enhanced procedures (e.g. enhanced CT scan, angiography, venography) are nephrotoxic and increases the risk of contrast-induced nephropathy (CIN).

• However, MALA risk is increased with serious concurrent illness such as sepsis, shock, hypovolemia, decompensated heart failure, or liver failure.

• Higher risk for MALA if AKI develops from CIN.

Canadian Association of Radiology guideline recommendations:

Signs & Symptoms:

• Reduced serum HCO3 and pH may be markedly or slightly low.

Hold metformin at time of contrast in eGFR <45ml/min and restart no sooner than 48h after if renal function is stable (<25% increase in baseline SrCr).

• Asymptomatic during mild acidemia but nausea, vomiting, malaise, hypotension, and shock may present with more severe acidemia (pH < 7.10).

Diabetes Care 2014 Oct; 37(10): 2864-2883.

• Hyperpnea

Oral Antihyperglycemic Options in CKD

Diabetes Care 2014;37:2291–5.

Lewis, J. Merck Manuals Online. 2016.

Can Assoc Radiol J. 2014 May;65(2):96-105.

Can J Diabetes 2013;37:S61eS68

Clinical Pearl:

Metformin should be held when there is a high risk of AKI such as sepsis, hypotension, acute MI, and use of radiographic contrast in CKD patients.

Learning Objectives

Bowel Cleansing Agents: Clinical Pearls

• To explain the mechanism by which NSAIDs contribute to acute kidney injury (AKI).

Polyethylene glycol (PEG or macrogols)

• To recognize the drug interaction between NSAIDs, ACE-Is, and diuretics that contribute to AKIs.

• Non-absorbable isosmotic solutions without net absorption or secretion; therfore, significant fluid and electrolyte shifts are attenuated. Preferred in CKD.

• To identify drugs that may increase the risk for AKI during acute illness and contrast procedures.

Metabolic Acidosis in CKD

• To discuss the role of sodium bicarbonate in delaying CKD progression.

• Low-volume PEG (2L) combined with bisocodyl or stimulant laxatives better tolerated than standard 4L. Some studies suggest no difference in cleansing efficacy.

• To select bowel cleansing agents for colon preparation that are safe in renal impairment.

• Metabolic acidosis is common in CKD due to impairment in urinary excretion of hydrogen ions in the form of titratable acids and ammonium with declining functional nephrons.

Electrolyte Supplementation

• To examine the evidence behind the association of proton pump inhibitors (PPIs) with CKD.

• Concern for volume contraction and electrolyte disturbance (hypokalemia, hyponatremia) after bowel prep use. Many products supplemented with electrolytes.

• Metabolic acidosis is associated with progression of CKD and increased mortality.

• To review the current evidence of sodium-glucose co-transporter 2 (SGLT-2) inhibitors and their impact on renal outcomes in type 2 diabetics.

Usual dose: NaHCO3 0.5 to 1 meq/kg/day

1g of NaHCO3= 12mEq of Na+ and HCO3-

• Reported incidence of hypokalemia (K+ <3 mmol/L) in patients taking PEG preparations after colonoscopy highly variable~ 9.6 to 56%. Unknown incidence in CKD.

• Other complications include:

- Protein energy wasting and malnutrition

Insufficient data to currently advise on electrolyte supplementation after bowel cleansing in CKD. Caution with preparations with electrolytes in patients with hyperkalemia. Consider baseline and post-treatment blood work for electrolytes.

- Decreased respiratory reserve and body buffer systems

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Ann Pharmacother 2010;44:466e70.

Gut. 2012 Nov;61(11):1525-32. Epub 2012 Jul 26.

- Exacerbation of anemia and secondary hyperparathyroidism

- Systemic inflammation

• Upper bound of target serum HCO3 unclear.

Risk for AKI during Acute Illness

- Increased risk for heart failure and osteopenia

Nephrol Dial Transplant. 2009 Apr;24(4):1232-7.

Nephrol Dial Transplant. 2009 Apr;24(4):1232-7.

Kidney Int. 2011 Feb;79(3):356-62.

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Oral Sodium Phosphate & Acute Phosphate Nephropathy

• Oral sodium phosphate previously used as bowel preparation but indication as purgative was removed in Canada in 2009 due to risk for acute phosphate nephropathy. Only marketed as laxative now.

Educate patients on potentially nephrotoxic agents or renally excreted drugs that should be held during episodes of acute illness.

Sodium Bicarbonate in Delaying CKD Progression

• Can cause volume contraction, transient hyperphosphatemia, and nephrocalcinosis.

2012 KDIGO Guidelines for CKD

No Conflicts of Interest

• Acute phosphate nephropathy also reported with sodium phosphate (Fleet) enema but rare. Association not clearly established.

• Randomized controlled trial (n=134) in stage 4 CKD with metabolic acidosis (baseline serum HCO3 16-20meq/L) demonstrated treatment with oral NaHCO3 600mg po tid titrated to achieve serum HCO3 of 23 meq/L or higher resulted in lower mean rate of CrCl decline (1.88 vs. 5.93ml/min per year) and ESRD (6.5 versus 33%) vs. no treatment.

Consider avoiding both sodium phosphate oral solution and enema in CKD for laxative use given availability of safer alternatives.

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J Am Geriatr Soc. 1992 Jun;40(6):620-1.

http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2009/14562a-eng.php

Claudia Ho BSc. Pharm, ACPR, PharmD (candidate)

Clinical Pharmacy Specialist, Fraser Health Renal Program

Claudia.Ho@fraserhealth.ca

To access presentation online, GOOGLE search: prezi claudia ckd

2012 KDIGO Guidelines for CKD

Proton Pump Inhibitors (PPIs): Harm in CKD?

• Systematic review of 9 observational studies found significantly higher risk for AKI and CKD in PPI users vs. non-PPI users but based on low quality of evidence.

Observational evidence demonstrated triple combination was associated with ~30% increased risk, which peaked within the first 30 days of use.

Limitations:

NSAIDs with half-lives ≥ 12 hours were associated with higher risk of AKI in triple combination.

• Confounding by indication- non-PPI group likely healthier vs. PPI group, H2RA antagonists not valid comparators

Clinical Pearls

• Baseline characteristics not available for all studies- unable to adjust for baseline differences of eGFR and elevated albuminuria

• Avoid triple combo in patients with risk factors for AKI such as elderly, diabetes, CKD, ascites, or heart failure.

• Several studies allowed for concomitant nephrotoxic medications such as NSAIDs.

• Consider NSAID alternatives such as acetaminophen, tramadol, or short-term use of opioid. Topical diclofenac is acceptable since little is absorbed systemically.

Nephrol Dial Transplant. 2017 Feb 23. doi: 10.1093/ndt/gfw470.

• If NSAIDs must be used, avoid those with long half-lives (e.g. naproxen, meloxicam, piroxicam).

Current evidence insufficient to demonstrate causal link between PPIs and development of CKD. Possible association but based on low quality of evidence.

Nephrol Dial Transplant. 2017 Feb 23. doi: 10.1093/ndt/gfw470.

Nephrol Dial Transplant. 2017 Apr 1;32(suppl_2):ii40-ii46.

• Avoid dehydration during acute illness. If patient is dehydrated, hold the diuretic until intravascular volume is replenished. Also, hold ACE-I or ARB until volume has normalized and patient is no longer hypotensive.

BMJ. 2013 Jan 8;346:e8525.

Cochrane Database Syst Rev 2012;9:CD007400.

Pharmacist's Letter April 2014 #290408

De-prescribing tools available at deprescribing.org

So What do We do With PPIs?

• >50% of PPI prescribed are inappropriate or unnecessary, especially in the elderly.

Other Potential Risks...

• Risk for increased bone fractures, C. Difficile infection, and hypomagnesemia recognized by both FDA and Health Canada.

• Several observational studies suggest association with community acquired pneumonia, spontaneous bacterial peritonitis and dementia .

However, study findings should not deter from PPI use where medically indicated, but should trigger clinicians to regularly review indication for PPIs and de-prescribe as appropriate.

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http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/26523a-eng.php

http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm213259.htm

The "Triple Whammy" Drug Interaction

• "Triple whammy" = combination of an ACE-inhibitor (ACE-I) or ARB, a diuretic and NSAID, which increases the risk of AKI by reducing renal perfusion.

NSAIDs can raise blood pressure, cause fluid retention, and worsen renal function in patients with hypertension, heart failure, diabetes, and CKD.

Effect of each drug on glomerular hemodynamics:

• ACE-I or ARB: reduces glomerular filtration pressure via vasodilation of the efferent arteriole.

• NSAID: reduce blood flow to the glomerulus by inhibiting production of vasodilating prostaglandins.

Conditions Causing Hypoperfusion:

• Hypotension
• Renal arterial disease
• Dehydration
• Congestive Heart Failure

• Diuretics: reduce blood flow to the glomerulus via intravascular volume depletion.

Br J Clin Pharmacol 2005;59:239-43.

BMJ. 2013 Jan 8;346:e8525

NaHCO3 Monitoring & Patient Education

Adverse effects:

• Belching, gastric distension and flatulence due to CO2 released in stomach.
• Rarely causes metabolic alkalosis (higher risk during vomiting, diarrhea, and hypokalemia)
• Exacerbation of heart failure, edema

Drug interactions:

• Concomitant use of NaHCO3, non-absorbable antacids (aluminum, calcium, magnesium carbonate), and cation-exchange resins (Kayexalate) increases metabolic alkalosis risk.

• Management: Space Kayexalate at least 2 hours apart from antacid or switch antacid to alternative such as H2 receptor antagonists.

• Use of NaHCO3 and calcium (1.5 to 2g elemental/day) together can increase risk for milk-alkali syndrome but is uncommon.

Counsel patients to avoid taking NaHCO3 simultaneously with other medications (1-2h interval recommended) due to possible alteration of absorption.

Clin Endocrinol (Oxf). 2005 Nov;63(5):566-76.

Kidney Int. 2014 Mar;85(3):529-35. doi: 10.1038/ki.2013.401.

The Hype with SGLT2 Inhibitors

New Kids on the Block: Sodium-Glucose

Co-Transporter 2 (SGLT2) Inhibitors

EMPA-REG OUTCOME trial

Currently 3 agents available on the Canadian market:

• Empagliflozin (Jardiance)
• Canagliflozin (Invokana)
• Dapagliflozin (Forxiga)

Empagliflozin shown to slow progression of nephropathy in T2DM with CVD, when added to standard care (e.g. ACE-I/ARB, statin, metformin) in patients with at least eGFR of 30 ml/min or higher.

Mechanism of Action:

• Inhibits SGLT2 in the proximal renal tubules, which reduces reabsorption of filtered glucose and leads to increased urinary excretion of glucose.

• Over 3 years, prevented new or worsening nephropathy* (NNT=16) and included patients with normo-, micro-, and macroalbuminuria at baseline.

• Less progression to macroalbuminuria (NNT= 20)

• Less doubling of SrCr (NNT= 90)

• Less initiation of renal-replacement therapy (NNT=333)

Should SGLT2 inhibitors be the preferred agents in CKD for diabetes management?

N Engl J Med. 2015 Nov 26;373(22):2117-28.

*Defined as progression to macroalbuminuria, doubling of SrCr, initiation of renal-replacement therapy, or death from renal disease.

Diabetes Ther (2014) 5:355–366

Common Medications Encountered in Non-Dialysis Chronic Kidney Disease: Minimizing Drug-Induced Harm and Delaying Progression

Questions?

Not all SGLT2 Inhibitors are Created Equal...

Oct 2015 Health Canada Post-Market Safety Review- reports of acute kidney injury and renal impairment requiring hospitalization and dialysis with both canagliflozin and dapagliflozin. Empagaflozin was just marketed Aug 2015.

Jan 2017 Network and cumulative meta-analysis of RCTs

• Only empagliflozin was associated with lower risk for acute renal impairment/failure vs. placebo (OR 0.72, 95% CI 0.60-0.86).
• Dapagliflozin was associated with greater risk of composite renal outcomes* vs. placebo (OR 1.64, 95% CI: 1.26-2.13).

More trials needed but empagliflozin renal benefits likely not a class effect. Empagliflozin would be the preferred SGLT2 inhibitor among its class.

SGLT2 inhibitors associated with other adverse effects (e.g. diabetic ketoacidosis, genitourinary tract infections) and currently still considered as add-on therapy for T2DM.

* Definition of outcomes were not clearly specified (increased SrCr/BUN, decreased eGFR, renal impairment, and renal failure).

Diabetes Obes Metab. 2017 Feb 27. doi: 10.1111/dom.12917.

http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/sglt2-eng.php