Renal 2 Flashcards
1
Q
Epidemiology of CKD in Canada
A
1 in 10 Canadians live with CKD (~ 4 million people)
2
Q
What is the leading cause of CKD?
A
Diabetes is the leading cause of CKD (38%)
3
Q
Canada and ESRD Stats
A
End-stage renal disease ↑ 35% since 2009
In 2018, CKD was the 10th leading cause of death in Canada
4
Q
Can CKD be managed within primary care?
A
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
5
Q
Clinical practice guidelines are developed by…… Key consideration of the interpretation of the guidelines?
A
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
6
Q
Define CKD. What is it charcterized by and briefly discuss its progression?
A
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)
7
Q
CKD is a leading cause of _________ in North America because of……
A
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
8
Q
What is the leading cause of mortality regarding CKD? Stats?
A
Cardiovascular disease
–> Leading cause of mortality
50% of deaths of those with CKD are a result of cardiovascular disease (arrythymia or death)
9
Q
What are some causes of CKD?
A
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
10
Q
What are some high risk CKD populations?
A
Hypertension (HTN)
Diabetes Mellitus
Cardiovascular Dx
First degree relative with CKD
First Nations, Inuit, Metis or urban indigenous people(s)
11
Q
What is the relationship between Indigenous people and the prevalence of CKD?
A
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
12
Q
The clinicical definition of CKD is…..
A
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
13
Q
What is the issue with defining CKD just based off of kidney function (GFR)
A
** Remember low eGFR may be explained by an AKI – may need to rule-out **
Impairment for 3 months or longer –> two tests
14
Q
Criteria for CKD:
A
15
Q
Screening of CKD algorithm
A
Recommended to order a lab panel of GFR should be done annually
16
Q
Describe the rate of decline of GFR
A
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”
17
Q
What are some risks associated with CKD in older adults?
A
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)
18
Q
Describe the staging of CKD based off of GFR:
A
G1 and G2 are not apart of CKD
19
Q
Describe the staging of CKD based off of albuminuria:
A
A1 is not diagnostic of CKD
20
Q
Regarding GFR and albuminuria classification, what is something that should be considered?
A
Regardless of the disease state causing CKD, the staging applies
21
Q
Why is screening of CKD is important?
A
CKD is often asymptomatic
–> Importance of screening
22
Q
Describe the onset of sx of CKD
A
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
23
Q
Describe the onset of CKD and diabetes
A
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
24
Q
Describe an overview of the care facilities in which CKD is managed
A
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
25
Overview of Care for CKD
Delay progression of CKD
CV risk reduction
Treat complications of CKD
Renal replacement therapies (RRT)
26
Are all causes of CKD progressive?
Once CKD develops, it generally progresses over time
Autoimmune CKDs may undergo remission (e.g. lupus)
27
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
28
What is the general concept around GFR decline in tx of CKD?
Can slow the progression; cannot truly prevent the progression
29
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
30
What are some non-modifiable factors associated with faster progression of CKD?
Non-modifiable:
African-American race
Male gender
Advanced age
Family history
31
What are some modifiable factors associated with faster progression of CKD?
Modifiable:
Uncontrolled hypertension
Poor blood glucose control
Proteinuria
Smoking
Obesity
32
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
33
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
34
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
35
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
36
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
37
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
38
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%
39
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.
.
40
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
41
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
42
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
43
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%
44
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)
45
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
46
According to the SPRINT trial, what were some reasons favouring a SBP target of less than 120?
1. The potential benefits are clinically meaningful (Statistical significance in composite endpoint of CV events and all cause mortality)
2. The CV and mortality benefit may make it worth trouble shooting tolerability and adverse event risks for some patients.
47
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)
48
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
49
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
50
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
51
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
52
Blood pressure control in CKD can be difficult because....
Often require 3-4 drugs to control BP, especially as kidney disease progresses
53
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
54
What is the first line tx for HTN if a patient has proteinuria?
ACEi and ARBs
55
Describe the RAAS pathway and where ACEi and ARBs work
Angiotensin Coverting Enzyme released by lungs
56
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
57
What is unique about ACEi and ARBs in CKD?
Reduce proteinuria more than any other antihypertensive
58
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
59
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)
60
HTN Canada and KDIGO recommend an ACEi or ARB as....
First-line therapy for kidney diseases with albuminuria
61
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)
62
Is there preference given to an ACEi or ARB?
No. Can be used interchangeably.
63
What are some contraindications for ACEi/ARB therapy?
Angioedema
Bilateral renal artery stenosis
Pregnancy
64
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
65
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+)
66
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)
67
How critical is the monitoring of ACE/ARB therapy in CKD?
CRITICAL IN CKD
VULNERABLE TO INCREASES HERE
MONITORING BECOMES IMPORTANT
68
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
69
Describe the algorithm for monitoring of SCr and K+ in CKD for ACE/ARB therapy?
KDIGO
70
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
71
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
72
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)
73
ACEi end in....
PRIL
74
ARBs end in
SARTAN
75
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)
76
A direct renin inhibitor is.....
Aliskiren
77
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
78
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
79
Steroidal MRA's are also known as..... Examples
Steroidal (aka non-selective)
Spironolactone, eplerenone
80
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)
81
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
82
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)
83
What was the main finding of the FIDELO-DKD trial?
The most concerning a/e of Finerenone was hyperkalemia
84
According to KDIGO DM recommendations of MRA usage, what are the guidelines for therapy regarding K+ lab values?
85
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)
86
Why are diuretics used in CKD?
Fluid retention is an important contributor to hypertension in CKD
Most patients require diuretic therapy
87
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
88
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
89
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
90
CCB used in CKD
DHP-CCB's - e.g. Amlodipine
Non-DHP CCBs - Diltiazem, Verapamil
91
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
92
DHP-CCB A/E in CKD
May cause fluid retention and edema (problematic in CKD patients)
Pedal edema; peripheral vasodilation, leakage into extravascular peripheral space (NUISANCE SIDE EFFECT; NOT A BIG PROBLEM)
93
NON-DHP CCB Use in CKD
Shown to decrease proteinuria, but not to same extent as ACEIs
Not preferentially used for reducing proteinuria, but may provide benefit when added to ACE-i/ARB
No evidence for slowing CKD progression
94
Tolerability and Safety Issues with Non-DHP CCB's
constipation and bradyarrhythmia
(particularly in combo with BBs)…lots of DIs, CIs
95
Dose Beta-Blocker in CKD
Renally eliminated BBs may require dosage adjustment once CrCl approaches 30 mL/min
E.g., atenolol, bisoprolol
96
Monitoring of Beta-Blockers
Monitor HR and BP for signs of accumulation
97
Common s/e of Beta-Blockers
Common S/E: fatigue, limited exercise tolerance
98
Why are beta-blockers used in CKD?
Inconsistent evidence that BB have evidence in CKD pt’s
Use if HF, Post MI, Angina
99
Alpha 2- Agonist Example
clonidine
100
Alpha-2 Agonist Use in CKD.WHy?
Valuable as adjunctive therapy for HTN b/c no DIs with commonly used BP meds
Blood pressure hard to control in later stages of CKD
101
Alpha 2 Agonist Precautions
Usual precautions due to CNS side effects (e.g., elderly)
Risk of rebound HTN if stopped abruptly (taper if discontinued)
102
Alpha-1 Blocker Examples
terazosin, prazosin
103
Alpha-1 Blocker Usage in CKD
Adjunctive treatment for elevated BP in CKD patients
Might consider in patient with prostatic hypertrophy (BPH)
104
Alpha-1 S/E
Common S/E: dizziness, orthostatic hypotension
105
Direct Vasodilator Example
Hydralazine
106
Direct Vasodilator Usage in CKD
Might be used as adjunct
Use is limited by side effects (e.g., headache, fluid retention)
107
Are SGLT-2i used in CKD for BP management?
Have some blood pressure benefit; not the main reason for why we use
108
Which agents used for BP management have an effect on CV or kidney function despite BP management?
ACEi
ARB's
NON-DHP CCB
Direct Renin Inhibitors
MRA's
All reduce proteinuria
109
Which agents used for BP management have an effect on kidney function? Mechanism?
ACEi
ARB's
NON-DHP CCB
Direct Renin Inhibitors (if not tolerating ACEi or ARB)
MRA's
All can reduce proteinuria
110
What is the relationship of proteinuria with CKD? CV DX?
Is linked with progression of diabetic and non-diabetic CKD
High risk of progressing to kidney failure
An indicator of subclinical cardiovascular disease
111
What category is micoralbuminuria classified as?
Category A2 albuminuria
112
What is the relationship between Micoralbuminuria and CKD progression? Why is this critical?
Predicts loss of kidney function
Important to identify patients at this stage so appropriate therapy (ACE-i or ARB) can be instituted to slow progression
113
Why is proteinuria damaging to the kidneys?
Cellular damage, damage to glomerulus, protein is toxic to the tubules
114
What is the definition of proteinuria? What proteins is it?
Proteinuria: > 150 mg protein lost in urine per day
Can be albumin OR other plasma proteins
115
Describe the classification of proteinuria
Mild (150–500 mg) = Category A2
Moderate (>500 mg) = Category A3
Nephrotic range (more than 3000 mg = 3 grams or albumin excretion > 2200 mg/24h)
116
What is the normal amount of protein lost in the urine throughout the day?
40-80 mg per day is a normal amount of protein in the urine
117
Why are proteins in the plasma critical?
Protein through osmotic effect maintains fluid in vasculature; lose proteins in urine, decrease blood pressure
118
What is nephrotic syndrome?
Associated with hyperlipidemia, hypoalbuminemia, generalized edema, thromboembolic risk (Anti-thrombin 3 lost in urine- clot risk increases)
foamy urine
119
What are some examples of kidney diseases associated with proteinuria? TX?
Diabetic nephropathy
Hypertensive kidney disease
Primary glomerular diseases (e.g., Minimal Change Disease, focal and segmental glomerulosclerosis, IgA nephropathy)
Lupus nephritis
Post-streptococcal glomerulonephritis
- For many an ACEi or ARB may be appropriate; but may not be started right away
- Many also treated with steroids or immunosuppressants
120
Why may an ACEi or ARB be used in pt's without HTN?
Reduce glomerular capillary pressure and volume (vasodilate efferent arteriol; less pressure; protective ebenfit)
Possible direct effect on podocytes to ↓ proteinuria
(Want to Reduce proteinuria in the absence of HTN because of the effect on the glomerulus)
121
ACEi and ARBs indication
First-line therapy for kidney diseases with proteinuria (due to CV and kidney benefits)
Diabetic or hypertensive kidney disease with category A2 or A3 albuminuria
Other kidney diseases with proteinuria
122
ACEi and ARB in patients with HTN and Proteinuria Monitoring
Monitor for hypotension
123
DAPA_CKD Trial looked at....
Dapaglifozin 10 mg vs placebo in patients with CKD with or wt diabetes
124
Findings of DAPA-CKD
Irrespective of diabetes:
Decline in ESRD and death from CV or renal dx (driven by preservation of eGFR)
Prevention of decline in eGFR > or = 50%
Decline in all cause mortality
Those without diabetes had no hypoglycemic risk
125
DAPA-CKD Main A/e
Volume depletion
126
What is an issue with the DAPA-CKD trial?
98% were on ACEi or ARB
65% were on a Statin
- Difficult to determine the effect of dpaglifozin on its own
127
Indication SGLT-2i in CKD (CCS) Why?
CanadianCardiovascular Society
- - Adults with ACR >20 mg/mmol and eGFR >or = 25%
- Reduce significant decline in eGFR, ESRD, death due to renal dx or CV all cause CV mortality
- reduce nonfatal MI and hospitlization for HF
128
Bottom line of SGLT-2i usage in CKD
You will see prescriptions for SGLT2i in patients with CKD and withOUT diabetes!
To improve renal and CV outcomes
129
Limitations of SGLT-2i use in CKD
Limitations: COVERAGE
Dapa has the best coverage on SK formulary (coverage for CKD without diabetes); NIHB open coverage
130
what is the relationship between T2D and CKD?
40% of patients with T2DM have CKD
131
Is screening for CKD recommended for diabetics? If so, when?
Screening for CKD in patients with diabetes:
Random urine ACR & SCr (and eGFR) should be checked at least annually in stable patients
Begin screening:
5 years after diagnosis of T1DM
At time of diagnosis for T2DM
132
Is diabetes Canada guidelines on nephropathy the same as KDIGO?
NO
133
CKD progression in Diabetes
Progresison is typically slow; 5 years in each stage
Slow at the beginning; 1-2 ml per year, accelerates in later years 5-10 ml per year --> Quickly leads to ESRD
- Why screening is important
134
Why is blood glucose control critical in diabetics?
Prevents and delays progression of diabetic nephropathy
135
A1C targets for reducing CKD risk in Diabetics
Target A1C ≤7.0 for most patients
≤6.5 may be appropriate in some to ↓ CKD risk
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Why may an agressive A1C target be used? Risks?
Slow down other risks such as nephropathy however run the risk of hypoglycemia
New medications have a lower risk of hypoglycemia so may pursue more aggressive targets
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Issues with A1C Measurements in CKD
HbA1C measurements may be less accurate in patients with advanced CKD (~G4 – G5, particularly with dialysis)
Develop significant anemia, blood loss, etc.
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Why are higher A1C targets, such as 8, not useful in CKD?
- KDIGO
- Increase in severity of CKD
- Macrovacular compl present
Many commorbities
Short life expectancy
Impaired hypoglycemia awareness
Scarce resources for hypogycmeia managment
More risk of tx induced hypoglycemia
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KDIGO TX Algorithm for Diabetes
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Metformin Use in Diabetics with CKD
Evidence primarily for CV benefit
Lack of evidence for kidney protective effects other than lowering A1C (not kidney protective)
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What are some benefits of metformin?
Low risk of hypoglycemia, inexpensive drug, weight loss (bare minimum are weight neutral), good safety profile
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Diadvantage of Metformin
Requires Renal Dose Adjustments
- Dose is lowered at a GFR of <45 ml/min
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Why does metformin require dose adjustments at a GFR below 45 ml/min? Exception?
- Lactic Acidosis
- High mortality rate
May see used in individuals with STABLE renal function with eGFR 15-29 ml/min (500 mg/day)
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SGLT-2i Evidence in Diabetics with CKD
Evidence for CV benefits AND for reducing the progression of CKD in patients with DM
CREDENCE 2019 (DM, albuminuria): canagliflozin
DAPA-CKD 2020 (+/- DM, albuminuria): dapagliflozin
EMPA-KIDNEY 2022 (+/- DM, +/- albuminuria): empagliflozin
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KDIGO reccomendation for use of SGLT-2i in Diabetes
1st line agent for patients with T2DM, CKD, and eGFR >20mL/min
- Have not said to use in pt's without diabetes yet
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SGLT-2i Benefit is independent of.....
Independent of glucose lowering effect
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What is the action of SGLT-2i on the kidney? Clinical implications?
Afferent arteriole narrowing leads to:
a) Decreased glomerular pressure
b) Reduction in albuminuria
c) Renal protection suggested
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What is the action of RAAS blockade on the kidney? Clinical Implications?
Efferent arteriole widening leads to:
a) Decreased glomerular pressure
b) Reduction in albuminuria
c) Renal protection proven in clinical trials
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What is the benefit of SGLT2-i and RAAS blockade on the kidney?
- Afferent narrowing and efferent widening leads to:
a) Potential for normalization of intraglomerular pressure
b) Potential additive intraglomerular pressure reduction
c) Potential for long term renal protection
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Key Point of SGLT-2i usage in CKD
Guidelines recommend
SGLT2 inhibitors to improve
renal and CV outcomes,
regardless of the patient’s A1C
(even if targets are met)
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If we were to be worried about glucose in someone who had TD2M and CKD, what may we do?
Stop sulfonurea, gliclazide if worried about glucose and start an SGLT-2i
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Downfall of SGLT2-i in these pt's who have CKD
Benefits unkown
T1DM
GFR <20 ml/min
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Dapaglifozin Dose and Kidney Function Approved by FDA
Dapa- 10 mg OD - eGFR > 25 ml/min/1.73 m2
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EMpaglifozin Dose and Kidney FUnction Approved by FDA
10 mg OD (Can increase to 25 mg OD if needed for glucose control)
eGFR > or = to 30 ml/min for T2DM and ASCVD; 20 ml/min for HF
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Canaglifozin Dose and FDA Approved Renal Function
100 mg OD
eGFR > or = 30 ml/min
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Main Considerations in Initiation of SGLT-2i in CKD
KDIGO
Not to be initiated if eGFR <20mL/min, but may be continued until dialysis
Can continue with a modest initial ↓ eGFR (≤30%)
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Dosing of SGLT-2i? Is a dose increase required?
- Want to use the lowest dose possible for renal and CV benefits
- Limited benefit to increasing dose (Exception: if needing glucose control)
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With an ARB, AcEi, or SGLT2-i, why may one notice an initial decrease in eGFR?
Similar to ACEi and ARB reduce pressure on glomerulus leading to an increase in serum creatinine; expect with SGLT2i
Hemodynammaic increase here
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Effect of SGLT2-i on Dialysis
- Delays dialysis by 10 years if on SGLT2i
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Caniglifozin CI
eGFR <30 ml/min
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Dapaglifozin C.I.
eGFR < 25 ml/min
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EMpaglifozin C.I.
eGFR <20 ml/min
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Cautions of Initiating SGLT2-i. When to start?
- Volume depletion
- Active genital mycotic infection
- Hypotension (blood pressure less than 95 mmHG)
- Previous critical limb ischemia
- DKA
- Use of insulin or insulin secretagogues in those with GFR > or = 45 ml/min
DELAY INITIATION OF SGLT-2I UNTIL CONDITION RESOLVED/THERAPIES MODIFIED TO REDUCE RISK
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SGLT-2i drug-drug effects with:
Loop Diuretics
- Optimal dose reduction if euvolemic
- 30-50% dose reduction if volume depletion occurs (e.g. diziness)
Insulin or Insulin Scertagogue
- If DM with A1C < or = 8%, consider dose reduction (10-20% insulin or 50% secretagogue)
- if episodes of hypoglycemia, stop secretagogue and reduce insulin dose
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How do SGLT-2i work?
- Eliminates glucose in the urine so risk of volume depletion (hypovolemia)
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SGLT2-i MOA, GFR and A1C relationship
As GFR drops, the ability to reduce A1C is also lowered (eliminating glucose in the urine)
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Common A/e of SGLT-2i
Thirst
Increased Urinary Frequency and Urine Volume
Genital Mycotic Infections
Hypovolemia
Light headnessness and postural hypotension
Diabetic ketoacidosis
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How can one reduce the risk of diabetic ketoacidosis?
Hold in acute sickness
SADMANS
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Can an SGLT-2i cause an AKI?
Risk is low and has not been well observed
Predispose the kidney to hemodynamic effects (pre-renal effects)
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GLP-1 Agonist Examples
"Glutides" Example: Semaglutide
Exenatide and Lixsenatide
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Use of GLP-1 agonists in CKD
Evidence for CV benefits and favorable kidney benefits
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GLP-1 Agonist and KDIGO Recommendation
Use if A1C targets not achieved with metformin/SGLT2i (or if one of these not tolerated)
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Benefits of GLP-1A Agonists
Weight Loss
Insulin Sparing
CV Benfits
Quite effective at lowering A1C
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A1C comparison between SGLT-2i and GLP-1 Agonist
GLP-1's are quite effective at lowering A1C whereas SGLT-2i are less effective
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Limitations of GLP-1 Usage
Limited by cost; coverage is poor
Studies have been done for hardpoints have been done only with those with diabetics --> evidence only supports diabetics at the moment
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Medications used for blood glucose lowering that have cardiorenal benefits
SGLT-2i and GLP-1 agonists
- The rest of the diabetic medications are a toss up; e.g. sulfonureas have no CV or renal benfit; main benefit is only A1C lowering
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Why is smoking cessation critical for CKD?
Smoking increases progression of CKD
Mechanisms: ↑ BP & HR, ↓ renal blood flow (constriction), vascular injury
Also is a risk factor for cardiovascular events
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Regarding CKD, a critcial factor is...... Examples include:
Avoid use of nephrotoxic drugs whenever possible
Examples:
NSAIDs, COX-2 inhibitors
lithium
aminoglycosides
amphotericin B
calcineurin inhibitors
cisplatin
Minimize/avoid radiocontrast dye
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What combination should be avoided in CKD?
Avoid combination of ACE-i/ARB, NSAIDs, and diuretic (“triple whammy”)
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What is sick-day management?
When patients with CKD become acutely ill and are unable to maintain adequate fluid intake (e.g., due to viral gastroenteritis), recommended to hold potentially nephrotoxic or renally excreted drugs
Sulfonureas
ACE inhibitors
Diuretics, direct renin inhibitors
Metformin
Angiotensin receptor Blockers
NSAIDS
SGLT2-i
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Why is sick day management critical?
Largely around the kidneys
Input does not equal the output; susceptible to pre-renal AKI’s
Hold drugs that are nephrotoxic or renally eliminated
Metformin and sulfonurea are on here; can accumulate if not cleared as primarily cleared by the kidney
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What is the leading cause of death in people with CKD?
Cardiovascular disease (CVD) is the leading cause of death in patients with CKD
Most patients with CKD will die from CVD before requiring RRT
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WHat should people with CKD be screened for? Examples?
Patients with CKD should be screened for CV risk factors and managed appropriately
Common CV risk factors: DM, dyslipidemia, HTN, LVH, smoking, obesity
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CKD and CV Risk reduction: Which is first?
Main focus: Slow CKD progression then reduce CV risks
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Guidelines for starting Statin in CKD
CanadianCardiology Society
Age > or = 50 yrs old and eGFR <60 ml/min
or
ACR > 3g/mmol
Start a high dose statin in CKD despite baseline LDL level
- CKD is a statin indicated condition
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Key Point of Statin Use in CKD
Guidelines recommend a statin for most patients with CKD, regardless of their LDL
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KDIGO recommendations for the treatment of Dyslipidemia
> 50 years old with eGFR <60 & not on dialysis:
Tx with low-dose statin or statin/ezetimibe combo irrespective of LDL level
> 50 years old with CKD and eGFR >60:
Tx with statin
18–49 year old with CKD:
Tx with statin treatment if estimated CV risk is >10% (high) (e.g., prior CV event or diabetes)
If on dialysis: Do not initiate therapy - If already on therapy, continue it
Kidney transplant: Tx with a statin (in some cases)
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KDIGO Guidelines for Low or High Dose Statin
Stick with low dose statin
‘fire and forget’ strategy vs. ‘treat to target
- Not dosing based off LDL target
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KDIGO Benefit of Statin Use
Benefit = CV risk reduction and mortality, no benefits to slowing CKD progression (entirely cardiovascular)
- Relative risk similar in those with CKD and those without CKD; however, absolute risks in CKD group are higher so see a greater benefit
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Dosing of Statins in CKD Limitation
KDIGO Major limitation: Studies done on patients with dialysis
Evidence to support these doses are not based off the trials that apply to majority of CKD patients (small proportion that end up on dialysis)
Lacking good evidence to support using statins for primary prevention in majority of CKD population
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SHARP Trial Findings
SHARP trial – simvastatin vs ezetimide, not a good quality study – unclear benefit of ezetimide and never use as monotx, primary prevention trial)
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Jupiter Trial Findings
JUPITER trial --> Rosuvaststain --> 20% of pts had CKD (made some inferences off of that)
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Why does KDIGO recommend low dose statins?
More conservative route as lack evidence.
Some concerns about toxicity, question the lack of evidence supporting high dose ststains in CKD
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CCS Dyslipidemia Guidelines CKD Statin Use. Why?
- High dose statin in all patients who meet the criteria for primary prevention (includes CKD)
- Weak recommendation: Higher statin used, more benefit
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High Dose Statin Examples
Atorvastatin 40-80 mg HS
Rosuvastain 20-40 mg HS
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Which statins are hepatically eliminated?
Atorvastatin, lovastatin, and simvastatin
Hepatic Elimination (Concerns with Drug Interactions here)
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Renally Eliminated Statin
Rosuvastatin
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Can high doses of statins be used in CKD?
Doses can be used in all CKD pt’s even those with dialysis (studies in dialysis pt’s)
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When are statin's dosed?
DOSE HS
Cholesterol synthesis primary throughout the night
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Statin Tolerability Issues
Muscle pain; want a dose they can tolerate it.
Want someone on a high dose; however, want someone on the highest dose they can tolerate as a statin at any dose is better than no statin
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Main Safety Concern WIth Statins
Main Safety Concern with Statin’s: Rhabomyolsis --> Can lead to AKI --> Risk of rhabo is extremely low
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When choosing a statin in CKD, one may lean towards ______ because ______
Atorvastatin; hepaticl elimination
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Does anti-platlet therapy have a role in CKD?
Low dose ASA (81 mg) has no role in primary CV prevention in patients with CKD
Would be used in secondary prevention (post-MI etc.)
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What are the different types of renal replacement therapy?
Dialysis
Hemodialysis (HD) --- Intermittent HD
Peritoneal Dialysis (PD)
Continuous Renal Replacement Therapy (CRRT) --> Never used chronically
Kidney transplant
Preferred option for eligible patients (Reason: Mortality following kidney transplant is lower than those receiving dialysis)
Subject to organ availability
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What is a last resort option in ESRD if cannot do dialysis or kidney transplant?
Conservative, palliative care – manage the complications as best they can and live out life until death
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What is the most common dialysis?
Hemodialysis is the most common
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Dialysis Cost
Costs about 100,000 dollars a year to put someone through dialysis
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When is RRT initiated in CKD?
No set GFR at which RRT required (more guided by clinical status of pt)
Based on clinical status of the patient
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KDIGO recommendations for RRT in CKD?
Serositis (e.g., pericarditis- urea build up), acid-base or electrolyte abnormalities, pruritus
Inability to control volume status or BP (continuously fluid overloaded)
Malnutrition refractory to dietary intervention
Cognitive impairment (as a result of uremia)
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At what GFR is dialysis commonly required?
Most patients require RRT at GFR ~ 10 mL/min
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What is the main cause for dialysis in CKD? AKI?
Pt;s with CKD have to initiate dialysis due to uremia; where as AKI dialysis is more often due to issues with potassium or metabolic acidosis
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Most RRT Modality
Hemodialysis
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Hemodialysis MOA
Patient’s blood is passed through an external filter to remove wastes and fluid
Solutes move from the blood across the filter into the dialysis solution down their concentration gradient
Filtered blood is then returned to the patient’s body
Can be done at home or in a dialysis clinic
Replacement of chemicals such as sodium bicarb
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When is hemodialysis conducted?
Usually conducted 3x per week at the clinic
3-5 hours for each visit
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Benefits of Home Dialysis
Do it daily, connect themselves daily over night
Slower flow rate and better tolerated
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What does hemodialysis require for conduction?
Requires chronic vascular access that can withstand high blood-flow rates
Arteriovenous (AV) fistula (Preferred method – connect vein and artery mechanically)
Insertion of a synthetic AV graft
Catheter in neck --> Highest risks of complications
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What other med is needed in hemodialysis?
To prevent blood from clotting in the dialysis machine, patients require systemic anticoagulation during the procedure
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Hemodialysis Cautions
Massive fluid shifts during dialysis make patients more prone to hypotension (removing significant volumes of blood)
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Common Complications of Hemodialysis
Common: fatigue, hypotension, hypertension, cramps, N/V
Vascular access problems
Infection
Clotting
Bleeding
(More common with catheter than fistula)
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Special Considerations of Hemodialysis.Avoid? Monitor?
Water soluble vitamins are removed during treatment
All dialysis patients require a water-soluble vitamin formulation
Replavite® tablets (“renal vitamin”) – 1 tab PO daily
Avoid multivitamins containing minerals, vitamin A or D
Monitoring: serum folate, vitamin B12 every 6-12 months
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replavite
Replavite is really on its own; not interchangeable
Questionable how beneficial/necessary it is clinical
May be used in non dialysis CKD pt’s as well
All the B vitamins including biotin, small amount of vitamin C
Vitamin C in excess --> Form kidney stones, careful in these pt’s
Smaller quantities then seen in average multivitamins
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Peritoneal Dialysis relies on.... MOA
Relies on the patient’s own peritoneal membrane to act as a filter for fluid and wastes
2-3L of dialysate is instilled in the peritoneal cavity through an indwelling catheter in the abdominal wall
Wastes and fluid diffuse across the peritoneal membranes down their concentration gradient
Dialysate is drained and replaced with fresh solution
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Is peritoneal dialysis as efficient a shemodialysis?
Because blood is not in direct contact with membrane; less efficient
Has to occur daily, multiple times through a day
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Types of peritoneal dialysis
Continuous Ambulatory Peritoneal Dialysis (CAPD)
Manual exchange, usually 4-5 x per day.
Each exchange takes 30-45 minutes
Automated Peritoneal Dialysis (APD)
Automated – using a machine (called a ‘cycler’) while you sleep
Takes 8-10 hours
May also require manual exchange of fluid in abdomen during the day
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Advantage of Peritoneal Dialysis
Significant freedom; away from clinic, have flexibility
Typically only coming into CKD clinic every 1-2 months
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Clinical Benefit of Peritoneal Dialysis
Preserves residual kidney function; associated with better clinical outcomes in regards to mortality and other things as well
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Who is peritoneal dialysis good for? Who not?
May be preferable in patients continuing to work, travel, etc.
Less regimented schedule than HD
Patients must be able to perform self-care activities (adherent pt’s; unfortunately can be a significant challenge, training, etc.)
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Complication of peritoneal dialysis and treatment
Most frequent complication = Peritonitis
Inflammation and infection of the peritoneal lining
Treated with local or systemic antibiotics
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CRRT Use
Used in acute (intensive care) settings
Not suitable for chronic RRT
For patients who cannot tolerate the abrupt fluid shifts with intermittent HD (cannot be taking that much fluid off at once)
Recommended for hemodynamically unstable patients requiring RRT for an AKI
