Renal 2 Flashcards
Epidemiology of CKD in Canada
1 in 10 Canadians live with CKD (~ 4 million people)
What is the leading cause of CKD?
Diabetes is the leading cause of CKD (38%)
Canada and ESRD Stats
End-stage renal disease ↑ 35% since 2009
In 2018, CKD was the 10th leading cause of death in Canada
Can CKD be managed within primary care?
YES
95% of patients living with CKD are managed in primary care
Most people with CKD are asymptomatic
Appropriate to manage in primary care of CKD –> Send of those who have more substainial CKD to nephrologist
Clinical practice guidelines are developed by…… Key consideration of the interpretation of the guidelines?
KDIGO
Kidney Disease Improving Global Outcomes
Established 2003
International volunteer organization
KDOQI
Kidney Dialysis Outcomes and Quality Initiative
Established 1997
National Kidney Foundation (US)
Canadian Society of Nephrology
Guidelines updated in 2008 – CMAJ
Many of the recommendations are based on opinion or limited evidence given the lack of RCTs
Define CKD. What is it charcterized by and briefly discuss its progression?
Progressive loss of function occurring over several months to years
Characterized by gradual replacement of normal kidney architecture with fibrosis
Ultimately can progress to the point when dialysis or kidney transplantation is required
“End-stage renal/kidney disease” (ESRD or ESKD)
CKD is a leading cause of _________ in North America because of……
A leading cause of morbidity and mortality in North America due to:
Progressive loss of kidney function
–>Complications
–> Eventually require RRT
Cardiovascular disease
Leading cause of mortality
What is the leading cause of mortality regarding CKD? Stats?
Cardiovascular disease
–> Leading cause of mortality
50% of deaths of those with CKD are a result of cardiovascular disease (arrythymia or death)
What are some causes of CKD?
The two main causes of CKD are diabetes and HTN, which are responsible for up to two thirds of all cases
Immune and inherited causes as well a other reasons are responsible;e for the rest
Not one disease in isolation; an umbrella term that captures kidney dysfunction and the numerous conditions that may lead to it
What are some high risk CKD populations?
Hypertension (HTN)
Diabetes Mellitus
Cardiovascular Dx
First degree relative with CKD
First Nations, Inuit, Metis or urban indigenous people(s)
What is the relationship between Indigenous people and the prevalence of CKD?
Indigenous Peoples are disproportionately affected by DM and related complications
2.6 times higher rate of ESRD or death in First Nations vs. non-First Nations persons diagnosed with DM prior to the age of 20
The WHO has recognized colonization as the most significant social determinant of health affecting Indigenous Peoples worldwide
The clinicical definition of CKD is…..
Kidney function
GFR ≤ 60 mL/min/1.73m2 for 3 months or more,
with or without kidney damage
OR
Kidney structure
Kidney damage for ≥ 3 months, with or without decreased GFR, as evidenced by pathological abnormalities, abnormalities in blood or urine, or as seen by renal imaging
What is the issue with defining CKD just based off of kidney function (GFR)
** Remember low eGFR may be explained by an AKI – may need to rule-out **
Impairment for 3 months or longer –> two tests
Criteria for CKD:
Screening of CKD algorithm
Recommended to order a lab panel of GFR should be done annually
Describe the rate of decline of GFR
GFR ↓ by approximately 1 mL/min/1.73 m2/year beginning in the fourth decade of life (AT THE AGE OF 30)
65 yo ~50–60 mL/min.
80 yo ~30–40 mL/min.
GFR will ↓ to < 60mL/min in 5-25% of otherwise healthy adults due to aging alone (with no risk factors) –> NOT PREVENTABLE OR TREATABLE
Significant debate regarding labeling of patients >70 yo with mild to moderate reductions in GFR with no albuminuria and no hematuria as having “CKD”
What are some risks associated with CKD in older adults?
Reduced GFR due to age alone is not without risks:
Higher risk of AKI
Medication accumulation with reduced GFR (need for renal dose adjustments)
Reduced reserves in the event other comorbidities develop over time (e.g., DM)
Describe the staging of CKD based off of GFR:
G1 and G2 are not apart of CKD
Describe the staging of CKD based off of albuminuria:
A1 is not diagnostic of CKD
Regarding GFR and albuminuria classification, what is something that should be considered?
Regardless of the disease state causing CKD, the staging applies
Why is screening of CKD is important?
CKD is often asymptomatic
–> Importance of screening
Describe the onset of sx of CKD
Symptoms generally minimal in stages 1-2 and ↑ incidence in stages 3-4
Low energy, fatigue, confusion
Foaming, tea-coloured, blood or cloudy urine
Edema
Shortness of breath
Pruritis
Describe the onset of CKD and diabetes
First sign of CKD is albuminuria even when GFR is fine
Happens when sugars are poorly controlled; why we have the ability to diagnose both ways
Describe an overview of the care facilities in which CKD is managed
eGFR 30-59 mL/min (Stage 3a – 3b) –>usually managed in primary care
eGFR <30mL/min (Stage 4 – 5) –> usually managed in consultation with a nephrologist
Overview of Care for CKD
Delay progression of CKD
CV risk reduction
Treat complications of CKD
Renal replacement therapies (RRT)
Are all causes of CKD progressive?
Once CKD develops, it generally progresses over time
Autoimmune CKDs may undergo remission (e.g. lupus)
Describe the rate of decline of GFR in CKD
Rate of GFR decline highly variable from one individual to another
Average rate of decline between 2.3 to 4.5 mL/min/1.73m2 per year in the MDRD study
Lower GFR and greater albuminuria are both associated with a faster rate of progression
What is the general concept around GFR decline in tx of CKD?
Can slow the progression; cannot truly prevent the progression
Besides GFR, the rate of CKD progression also depends on…… Examples and rates?
Rate of progression also related to etiology of CKD
Diabetic nephropathy (with proteinuria occurs even faster), glomerular diseases, polycystic kidney disease, and kidney disease in transplant recipients tend to progress more quickly
Hypertensive kidney disease and tubulointerstitial diseases tend to progress more slowly
What are some non-modifiable factors associated with faster progression of CKD?
Non-modifiable:
African-American race
Male gender
Advanced age
Family history
What are some modifiable factors associated with faster progression of CKD?
Modifiable:
Uncontrolled hypertension
Poor blood glucose control
Proteinuria
Smoking
Obesity
What are some interventions to delay the progression of CKD?
Blood pressure control
RAAS blockade
–> ACE-i/ARB therapy
–> Non-steroidal MRAs
Blood glucose control in people with DM
–> SGLT2 inhibitors
–> GLP-1 agonists?
Smoking cessation
Avoidance of nephrotoxins
What is the relationship between hypertension and CKD?
Hypertension can be both a cause and a consequence of CKD
Develops in 60-90% of pts with CKD at any stage
Hypertension is associated with what in CKD? How is this managed?
Associated with faster progression of CKD as well as cardiovascular disease
Strict blood pressure control delays progression of CKD
Untreated HTN –> decline in GFR 12 mL/min/year
BP<130/80 –> decline GFR 1-2 mL/min/year
Describe the rate of decline in GFR as it relates to specific blood pressure values
Untreated HTN –> decline in GFR 12 mL/min/year
BP<130/80 –> decline GFR 1-2 mL/min/year
What are the blood pressure targets according to Hypertension Canada? What are these targets based off of?
<130/80 for patients with diabetic CKD
SBP <110 for adults with polycystic kidney disease
SBP <120 for “high risk” patients*
SBP <140 for “all other patients”
-Starredis based off of SPRINT trial
What are the KDIGO blood pressure targets?
SBP <120 for patients with high BP and CKD (not on dialysis), when tolerated (using standardized office BP measurements)
<130/80 for kidney transplant recipients
In the SPRINT trial, what was excluded from the inclusion criteria?
Diabetes Melitus
Looked at AARF
Age >75
Arthersclerosis
Renal CKD
Framinham Risk Score >15%
What is the benefit of the ACCORD trial?
ACCORD trial looked at more intensive of BP targets in diabetics (120 and 140)
Also looking at more aggressive A1C targets
No benefit to pursuing less than 120 and may result in harm in those folks
ACCORD did not recruit many patients with CKD because SCr >1.49 mg/dl was an exclusion criterion.
.
ACCORD Trial and KDIGO
More aggressive targets in diabetics
Looked at the subset of those with those with normal A1C targets, they did notice that more intensive lowering was beneficial (clouded in those with more aggressive lowering of A1C)
WhyKDIGO recommends less than 120 in those with diabetes
What trial was used in the development of HTN Canada Guidelines? Describe the hypertension Canada guidelines according to specific dx states?
SPRINT TRIAL
Patients meeting SPRINT criteria: <120 mmHG
Patients with Adult Polycystic CKD <110
All other patients with non-diabetic CKD <140
Critical consideration in the hypertension guidelines regarding blood pressure targets
A BP target may be individualized at the discretion of the physician considering:
a) Pt’s Specific Kidney Disease
b) Comorbidities
c) Age
What are some clinical indications for a systolic target of <120 according to the canadian hypertension guidelines?
a) Clinical or subclinical CV dx
b) CKD (non-diabetic nephropathy, proteinuria < 1 g/d, eGFR 20-59 ml/min/1.73 m2)
c) Framingham Risk Score > or = to 15%
d) Age > or = to 75
Patients with 1 or more clincial indications should consent to intensive tx
AARF
Age >75, artherosclerosis, CKD, Framingham >15%
What are some cautions for pursuing a SBP of <120?
Limited or No Evidence:
a) Heart Failure (LVEF < 35%) or recent MI in last 3 months
b) Indication for, but not currently recieving, a Beta-Blocker
c) Institutionalized elderly
Inconclusive Evidence :
a) Diabetes Mellitus
b) previous Stroke
c) eGFR <20 ml/min/1.73 m2 (Including dialysis and transplant pt’s)
What are some C.I. to pursuing a SBP of less than 120?
Patient unwilling or unable to adhere to multiple medications
Standing SBP <110 mmHg
Inability to measure SBP accurately
Known secondary cause(s) of HTN
According to the SPRINT trial, what were some reasons favouring a SBP target of less than 120?
- The potential benefits are clinically meaningful (Statistical significance in composite endpoint of CV events and all cause mortality)
- The CV and mortality benefit may make it worth trouble shooting tolerability and adverse event risks for some patients.
According to the SPRINT trial, what were some reasons against a SBP target of less than 120?
There are potential harms which must be weighed against the potential benefits including:
a) Syncope
b) Hypotension
c) Electrolyte abnormality
d) Acute renal failure
e) More CKD progression
A large number of the cases against SBP target is due to hemodynamic changes (change to renal blood flow and not actually damages to the kidneys itself)
Who may be suitable for a SBP target of <120?
Age >50 yo
W/out a high degree of comorbidity
Achieve BP control w/out requiring a large # of antihypertensives
Do not have issues with adverse effects
–> Those under 50 may still benefit; absolute risk reduction is highe rin those who are older
Who is not suitable for a SBP<120?
Age >90 yo, or living in a nursing home
Requiring > 3 antihypertensives to get to target
At risk of falls from postural hypotension
DBP < 60 mmHg (↑ MI risk?)
SBP 120-129 mmHg
Severe HTN (SBP > 180 mmHg)
Those who feel the benefits are not worth the risks, costs, effort
Lifestyle recommendations for lowering BP by HTN Canada?
Salt restriction: Reduce sodium intake towards 2,000mg (5g of salt) per day
Exercise: 30-60 minutes moderate intensity 4-7 days/week, in addition to the routine acts of daily living (higher intensities no more effective)
Weight reduction in overweight/obese pts
BMI 18.5-25 kg/m2 recommended
Limit alcohol consumption: 1-2 drinks/day
Describe the importance of lifestyle modifications in reducing BP as it relates to CKD?
NON-PHARM TX MUCH MORE IMPORTANT IN PT”S WITH CKD
Can be more beneficial than a drug and can decrease proteinuria
Blood pressure control in CKD can be difficult because….
Often require 3-4 drugs to control BP, especially as kidney disease progresses
First line options for blood pressure control per KDIGO? Considerations by pharmacists?
First-line options per KDIGO:
ACE-i/ARBs
diuretics
long-acting CCBs
Consider comorbidities, stage of CKD, degree of albuminuria, type of CKD when selecting therapy
What is the first line tx for HTN if a patient has proteinuria?
ACEi and ARBs
Describe the RAAS pathway and where ACEi and ARBs work
Angiotensin Coverting Enzyme released by lungs
Acei and ARB MOA in CKD
Reduce BP and glomerular capillary pressure
–> By selectively vasodilating the efferent arteriole
Reduce proteinuria more than any other antihypertensive
–> After accounting for the effect of BP lowering on protein excretion
What is unique about ACEi and ARBs in CKD?
Reduce proteinuria more than any other antihypertensive
How do ACE i and ARBs decrease proteinuria? This drives what decision?
Takes pressure off the glomerulus
Independent of BP lowering effects, ACE-I and ARBS reduce proteinuria by reducing pressure in the glomerulus
May even be used in those with CKD who have good BP control
Overall outcomes of ACEi and ARBs therapy in CKD?
Improvement in:
Kidney outcomes (e.g., reduced risk of kidney failure, doubling of SCr, GFR decline, progression of albuminuria)
CV outcomes demonstrated by multiple RCTs (e.g., IDNT, RENAAL, HOPE)
HTN Canada and KDIGO recommend an ACEi or ARB as….
First-line therapy for kidney diseases with albuminuria
When should an ACE/ARB be initiated in certain people according to HTN Canada and KDIGO?
Diabetic kidney disease – if ACR > 3mg/mmol (category A2, aka microalbuminuria)
Nondiabetic proteinuric CKD – if ACR > 30mg/mmol (category A3, aka macroalbuminuria)
Is there preference given to an ACEi or ARB?
No. Can be used interchangeably.
What are some contraindications for ACEi/ARB therapy?
Angioedema
Bilateral renal artery stenosis
Pregnancy
What is the concern with bilateral renal artery stenosis and ACE/ARB therapy?
Angiotensive 2 is protective of the kidney
–> allows filtration to occur and maintains perfusion especially in bilaterial renal artery stenosis
May see rises of SCr of greater than 30% in bilateral renal artery stenosis
DO not use
What are precautions for ACEi/ARB therapy?
Intravascular fluid depletion
–> Reduce/hold dose if severe vomiting, diarrhea, fluid depletion (May not be able to maintain perfusion)
eGFR <30mL/min/m2
Hypotension (caution if BP <110/70)
Hyperkalemia (K+ > 5.5 mmol/L) (inhibit the production of aldosterone; helps maintain K+, can see a rise in K+)
What are the monitoring parameters of ACE/ARB therapy?
2-4 weeks following initiation, or any dose ↑
SCr
↑ SCr > 30% from baseline may warrant discontinuation
Potassium (3.5-5mmol/L)
If high: restrict dietary K+, add diuretic
Blood pressure
Assess target achievement
Urinary Albumin: Creatinine Ratio (ACR)
How critical is the monitoring of ACE/ARB therapy in CKD?
CRITICAL IN CKD
VULNERABLE TO INCREASES HERE
MONITORING BECOMES IMPORTANT
If a patient is experiencing hyperkalemia, the pharmacist should….
DO EVERYTHING WE CAN TO REDUCE K+ BY OTHE RMECHANISMS RATHER THA STOPPING AND ACEI OR ARB
KEEP THEM ON BOARD
Describe the algorithm for monitoring of SCr and K+ in CKD for ACE/ARB therapy?
KDIGO
How are ACE/ARB’s dosed in CKD? Consideration?
Start at a low dose and titrate to maximum tolerated dose (or the highest approved dose
May have achieved targets of BP, may increase further to reduce proteinuria as much as possible
ACE/ARB Therapy Dose relationship with CKD progression
Dose-dependent reduction in the albuminuria lowering effect (and the risk of progression of CKD)
Side effects are also dose related
When selecting an ACEi or ARB, which ones should are choosen? Example?
If renally eliminated, must take into consideration
Monographs provide recommendations for decreased kidney function. Do not necessarily stop if kidney function is below and stable .
Perindopril –> if 25 ml/min(Do not use ifCrCl below 30) DO NOT STOP if kidney function is stable and doing well (DO NOT AUTOMATICALLY SWITCH ACE OR ARB BASED OFF WHAT THE MONOGRAPH IS SAYING)
ACEi end in….
PRIL
ARBs end in
SARTAN
Combination of ACE/ARB Therapy Recommendations. Why is this recommendation good or bad?
Combination of ACE-i + ARB used to be recommended for CKD with refractive proteinuria
Now, KDIGO recommends avoiding any ACE-i/ARB combination
Telmisartan, ramipril or both for preventing dialysis, renal transplant, doubling of SCr, or death
Combination superior for reducing proteinuria and BP, but actually worsened renal outcomes (hyperkalemia, need for acute dialysis)
A direct renin inhibitor is…..
Aliskiren
Aliskren Evidence for Use in CKD
Early trials - Alikirsen combination with ARBs, diuretics
Showed reduction in proteinuria
ALTITUDE TRIAL
patients with T2DM and proteinuria or CVD with reduced kidney function being treated with ACE-i or ARB
Measured CV and renal morbidity and mortality, compared with placebo, when added to conventional treatment (including ACE-i or ARB)
Aliskiren arm had more frequent adverse events, including non-fatal stroke, renal complications, hyperkalemia and hypotension
Aldosterone Antagonists (MRA’s)- Spironolactone Evidence in CKD
Mainly spironolactone + ACE/ARB in CKD (+/- DM) - Cochrane Review
Findings:
Reduced proteinuria 30-40%
Improved BP
Possible slowing of CKD progression (GFR decline)
No CV/ESRD outcomes (Not long enough to evaluate)
Doubled risk of hyperkalemia
5-fold risk of gynecomastia
Use of MRA’s limited to those who had another indication for it e.g. heart failure
Steroidal MRA’s are also known as….. Examples
Steroidal (aka non-selective)
Spironolactone, eplerenone
Non-steroidal are also known as….. Examples. MOA and use in CKD?
Non-steroidal (aka selective)
Finerenone
Much higher specificity for MR vs. glucocorticoid/androgen receptors
Reduction in albuminuria, while having less side effects (such as gynecomastia)
MRA Usage in DM Recommendation by KDIGO
Use non-steroidal MRA with proven kidney or CV benefit for patients with T2DM, an eGFR > or = 25 mL/min, normal K+ levels, and albuminuria (ACR > or = 3) despite maximum tolerated dose of a RAASi
–> Eligibility in trials was K+ < 4.8
MRA usage in HTN Recommendation in KDIGO
Possible use in refractory HTN (uncontrolled on 3 other drugs including a diuretic), with GFR >45 mL/min
All about blood pressure control (not a strong recommendation; a consideration)
What was the main finding of the FIDELO-DKD trial?
The most concerning a/e of Finerenone was hyperkalemia
According to KDIGO DM recommendations of MRA usage, what are the guidelines for therapy regarding K+ lab values?
What are some limitations of Finerenone
Not currently covered by SK drug formulary or NIHB
–> Approved by Health Canada October 2022, under brand name Kerendia
Less evidence available in patients also taking a SGLT2i
–> Benefits of finerenone appear to remain (indications but less confidence due to lack of evidence)
Not to use in combo with steroidal MRAs in patients with HF (and not to replace steroidal)
–> Lack of evidence and guidance to inform this decision; dependent on stage of HF (if less severe, may lean to use finerenone)
Why are diuretics used in CKD?
Fluid retention is an important contributor to hypertension in CKD
Most patients require diuretic therapy
Describe the initiation of a diuretic in CKD
Start with thiazide – might hear debate over efficacy once GFR<30 mL/min (stage G4-G5 CKD) –> may look to switch someone to a loop diuretic; may provide some blood pressure benefit through another mechanism at threshold of 30 ml/min
May switch to or combine with loop diuretics for volume control or if BP becomes resistant to therapy
May prefer combo with metolazone, chlorthalidone, or indapamide (effective diuresis at GFR<30 mL/min)
Generally avoid potassium-sparing diuretics in stage 3-5 CKD
Describe the CLICK trial
- Evaluated chlorthalidone efficacy vs placebo in stage 4 CKD (GFR 15-30 ml/min)
- 75% of people had T2DM
- Signficiant improvement in BP, 30-40% reduction in ACR
- Caveat: Short trial (12 weeks long) and did not look at hard endpoints
- Risks: Watch for electrolyte disturbances (e.g. hypok+) and orthostasis
Describe when a pharmacist would recommend a switch from hydrochlorothiazide to chlorthalidone
Hydrochlorothiazide signifificantly less potent than chlorthalidone (tzd)
If looking to start a diuretic on someone at 30 ml/min, start chlorthalidone
If GFR above 30 and good blood pressure control, would not likely switch them to chlorthalidone if on hydrochlorothiazide
CCB used in CKD
DHP-CCB’s - e.g. Amlodipine
Non-DHP CCBs - Diltiazem, Verapamil
DHP-CCB use in CKD
Preferred to thiazides in combo with ACE-i/ARB in patients with diabetes, given CV benefits (ACCOMPLISH TRIAL)
No evidence for slowing CKD progression
Is diabetes Canada guidelines on nephropathy the same as KDIGO?
NO
KDIGO TX Algorithm for Diabetes
