Managing complications of
therapy in CKD
Dr. Vincent Cheung
The Diabetes and Nephrology Symposium
November 19th, 2014
Disclosure
• Faculty: Dr. Vincent Cheung
• Relationships with commercial interests:
– Advisory Board Honoraria:
• Takeda
• Astra Zeneca
– Speakers Honoraria:
• Servier Canada
• Canadian Heart Research Centre
Disclosure of Commercial
Support
• This program may receive financial support from
Servier Canada in the form of an honorarium.
• Servier Canada products are not specifically
discussed in this program.
3
Diabetes and renal care
Outline
• Too wet too dry
• K+ Too high too low
• Hyperuricemia/Gout
Too wet too dry
“Bruce”, a diabetorenocardiopath
Bruce
•
•
•
•
73 years old
Type diabetes for 10 years
MI, PCI 3 years ago
Meds:
Ramipril 10 mg od
Amlodipine 10 mg od
Metformin 500 mg tid
Saxagliptin 2.5 mg od
ASA 81 mg od
Bruce
• Good diabetic control
• Recent cardiac testing – echo moderate
systolic dysfunction, no ischemia
• Presents with SOB, orthopnea, leg
swelling, weight gain of 15 lbs
Bruce
•
•
•
•
Furosemide 40 mg po od
2 days later no better
Furosemide increased to 80 mg od
Excellent urine output, feeling better after
4 days
• 3 weeks later, after weekend trip,
Furosemide “didn’t work”, weight up 12 lbs
in 2 days
• Furosemide increased to 120 mg bid
Bruce
• Excellent urine output, weight back down
after 4 days
• Furosemide reduced to 120 mg od
• 1 week later, diarrhea, weak, almost
fainted
• Seen in ER. Felt to be “dry”, Cr 244
• Furosemide, ramipril and metformin
stopped, IV fluid given, Cr down to 190
• Sent home within 24 hours
Bruce
• Feeling stronger, improved appetite
• Restarted on Furosemide 40 mg bid
• 3 days later back to ER with 14 lb weight
gain, SOB
Why is Bruce so unstable?
40 mg
120 mg bid
80 mg
190
185
180
120 mg
Weight in lbs
175
170
165
40 mg bid
160
155
Stopped
150
145
140
0
10
20
30
Days
40
Diabeto-renal concepts
Glycemic instability
Pushes glucose down
• Reduced intake
• Insulin/sulfonylurea
• Exercise
• BB, quinolones
• EtOH
Too high
Serum Glucose
Pushes glucose up
• Increased intake
• Insufficient insulin
• Inactivity
• Steroid, Thiazide
Too low
Why is volume so unstable
and what can we do about it?
•
•
•
•
•
•
•
•
Diet?  Na+ restriction/dietary routine
Ischemia?  Cardiac optimization
A Fib?  Rate control
NSAIDs/COX-2 inhibitors  Avoid
Other Na+ retaining meds – steroids, glitazones
Dehydration?  Sick Day Med Advice
Cardiac Output variation with volume status
Diuretic resistance
40 mg
120 mg bid
80 mg
190
185
180
120 mg
Weight in lbs
175
170
165
40 mg bid
160
155
Stopped
150
145
140
0
10
20
30
Days
40
Sick Day Medication Advice
• Pre-emptive temporary withdrawal of certain
medications during period of dehydrating illness
• Diarrhea, vomiting, poor intake
• Excessive heat exposure, bowel prep, high
output ostomy
• Instruct patients to stop ACE, ARBs, diuretics,
NSAIDs and NSAID creams to avert renal
failure, hypotension, hyperK+
• Can resume usual meds when better
40 mg
120 mg bid
80 mg
190
185
180
120 mg
Weight in lbs
175
170
165
40 mg bid
160
155
Stopped
150
145
140
0
10
20
30
Days
40
Cardiac Output
Frank-Starling curve
LV Filling Volume
Cardiac Output
Frank-Starling curve
LV Filling Volume
Frank-Starling curve
Cardiac Output
Normal
Heart failure
LV Filling Volume
Cardiac function and Volume
• Changes in volume status can result in
marked changes in cardiac output
• Reduction in cardiac output leads to heart
failure and renal dysfunction
• In decompensated heart failure patient
renal function may improve with diuresis
Advances in Heart Failure Therapy
•
•
•
•
•
•
•
•
•
ACE/ARB
Aldactone blocker
Cardio-selective beta-blockers
Antiarrhythmics
Implantable defribrillator
Cardiac resynchronization therapy
Valve repair
Revascularization
LV restoration
Furosemide
• Loop diuretic
• Introduced 1966
• Excretion 2/3 renal 1/3 hepatic
• Half life 100 minutes
Diuretic resistance
Dose response characteristic
• All or none response
• Dose threshold
Distal Adaptation
Breaking Phenomenon
NSAIDs
Urine production in 6 hrs
Furosemide dose-response curve
40
80
120
160
Dose
200
240
280
Urine production in 6 hrs
Furosemide dose-response curve
Worsening heart and/or renal function
40
80
120
160
Dose
200
240
280
Urine production in 6 hrs
Furosemide dose-response curve
40
80
120
160
Dose
200
240
280
Urine production in 6 hrs
A
B
C
40
80
120
160
200
240
280
Dose
Furosemide
Furosemide
changed
120from
mg in
80AM,
mg 40
po mg
to 40
in mg
PM po bid
What
What is
is the
the intention?
intention?
What will happen?
Adaptation
• Longstanding furosemide use can result in
hypertrophy of distal tubular cells
• Compensatory Na+ reabsorption occurs to
counter diuretic effect of loop
• Thiazide diuretics effective either as
permanent fixture of rescue therapy
Thiazides
Distal tubule
CA Inhibitors
Proximal tubule
5%
Antikaliuretics
70%
4.5%
Thick
Ascending
Limb
Collecting
duct
20%
100%
GFR 140 L/day
Plasma Na 140 mEq/L
Filtered Load 26,100 mEq/day
0.5%
Loop Diuretics
Loop of Henle
Volume 1.5 L/day
Urine Na 100 mEq/L
Na Excretion 155 mEq/day
From Knauf & Mutschler Klin. Wochenschr. 1991 69:239-250
Adaptations: Rebound sodium retention
“Breaking phenomenon”
Urine sodium , mEq/6 hr
300
F – Furosemide 40 mEq/d
250
200
150
100
50
0
F
F
F
F
Wilcox, et al, Kidney International 31:135, 1987
Why is volume so unstable?
Volume
Cardiac Output
Renal Function
Diuretic resistance
40 mg
190
120 mg bid
80 mg
185
180
120 mg
Weight in lbs
175
170
165
40 mg bid
160
155
Stopped
150
145
140
0
10
20
30
Days
40
Diabeto-renal concepts
• Sliding scale
– Strategy of prescribed proportional dosage
adjustments to provide acute correctional
action
• Target Weight
– Use of a set weight as a surrogate for optimal
body volume status
Diuretic sliding scale
• Escalating or declining loop diuretic dose
dictated by daily weight
• Can incorporate thiazide diuretic as
maintenance or rescue to counter
adaptation
• Can incorporate potassium supplement to
compensate for increased potassium
losses
• Patient feedback and self management
Diuretic Sliding Scale
FUROSEMIDE
No Furosemide, take in more salt
No Furosemide
80 mg in AM
80 mg in AM and PM
120 mg in AM and PM
160 mg in AM and PM
200 mg in AM and PM, call MD
167
168
170
173
176
179
180
ZAROXOLYN POTASSIUM
2.5 mg
5 mg
10 mg
A
B
Urine production in 6 hrs
WEIGHT
less than
167
to
169
to
171
to
174
to
177
to
greater than
C
40
80
120
160
Dose
200
240
280
1 tab
2 tabs
2 tabs
2 tabs bid
2 tabs bid
40 mg
190
120 mg bid
80 mg
185
180
120 mg
Weight in lbs
175
170
165
40 mg bid
160
155
Stopped
150
145
140
0
10
20
30
Days
40
Diuretic Sliding Scale
• Patient should weigh self daily, record weight
and follow scale instructions
• Once established need regular follow-up
• Volume check to adjust target weight
– Lean weight changes, constipation, amputation,
hardware
• Reassessment of diuretic response/threshold
“When you take your water pill(s), do you pee soon
after?”
Assessing Edema
Intravascular Expansion
– Sustained, not
intermittent
– Wt gain, SOB,
orthopnea
– History of cardiac
disease, high Na+
intake,
– Renal insufficiency
– JVD, creps, wheeze,
effusions
Vasodilatory
– Worse after prolonged
upright posture
– Better after prolonged
supine
– Worse with hot
weather
– Venous insufficiency
– Absence of other risks
or signs of volume
excess
K+ too high too low
40 mg
190
80 mg
120 mg
bid
K+ Too high Too
low
185
180
120 mg
170
6.0
6
165
Serum Potassium
Weight in lbs
175
5
40 mg bid
160
155
4
150 3
Stopped
3.2
2.8
145 2
140
0
10
20
30
Days
40
Potassium
• Disorders of potassium common in CKD
and DM
• Like glucose and volume, various factors
can drive potassium up or down
• Vigilance for these factors, frequent
checking and early corrective action can
improve K+ management
Diabeto-renal concepts
Potassium Balance
Pushes K+ down
• Reduced intake
• Loop/thiazide diuretics/steroids
• Kayexalate
• Diarrhea/vomiting
• Alkalosis
Too high
Serum Potassium
Pushes K+ up
• Increased intake
• ACE, ARB, Spironolactone, NSAID
• Sulfa
• Renal failure
• Acidosis
• Tissue breakdown, internal bleeding
Too low
K+ Management Tips
• Combining K+ sparing with K+ wasting
agents can aid in K+ balance
• Check K+ 2-3 weeks after change in
medication that can affect K+ handling
ACE/ARB, diuretic, NSAID, Sulfa
• Check K+ with worsening overload or
dehydrating illness
• Instruct patients on dietary K+
K+ Management Tips
• Replacement requires 80 – 100 mEq to
correct serum potassium by 1 mmol/L in
average sized person
• Kayexalate:
– 30 gm po will reduce serum K+ by about 0.3
mmol/L
– Excessive dose can cause hypoMg++,
hypoCa++, constipation
– Use may be limited by sodium load
Hyperuricemia
Urate 680
No history of gout or stones
Hyperuricemia
• Common in
–
–
–
–
–
Metabolic syndrome
Heart failure
Renal insufficiency
Alcohol use
Diuretic use
• Causes gout, uric acid kidney stones, urate
nephropathy
• Associations with hypertension, LVH, renal
decline in CKD, CV events, but treatment of
assymptomatic hyperuricemia not indicated
Uric Acid/Gout
• Anti-inflammatory treatment of acute gout
– NSAID
– Volume retention, renal dysfunction, peptic ulceration,
hypertension, increased CV risk
– Colchicine
– Diarrhea, sensimotor neuromyopathy, myelosuppression
– Corticosteroids
– Volume retention, hyperglycemia, thrush, peptic ulceration
– Weight gain, sleep disturbance
– AVN Hip, osteoporosis, cataracts
Uric Acid/Gout
• Anti-inflammatory treatment of acute gout
– NSAID
– Consider holding ACE/ARB during course
– Monitor volume and renal function closely
– Consider PPI
– Colchicine
– Give trial supply and plan B
– Corticosteroids
– Watch volume and glycemia
– Quick taper to low dose
– Consider PPI
Reducing Hyperuricemia
• Reduce diuretics, especially thiazides
• Consider once daily or alternate day loop
diuretic dose
• Low purine diet
• Weight loss/exercise
• Consider switching ACE/ARB to Losartan
Urate Lowering Therapy
• Allopurinol
– Dose 50 - 300 mg daily in CKD
– Can cause rash, pruritis, elevated LFTs,
hypersensitivity reaction
• Febuxostat
– For use if intolerant to Allopurinol
• Probenecid
– Uricosuric, use only with eGFR > 50
Urate Lowering Therapy
• Start 1-2 weeks after acute attack settled with
anti-inflammatory therapy
• Aim for uric acid level 360
• Continued anti-inflammatory prophylaxis for
6 – 9 months recommended to avert flare
• Continue ULT indefinitely
Am J Kidney Dis 47:51-59.
Summary
Multiple factors in diabetorenocardiopath
patients conspire to cause instability in
volume and potassium status.
Strategies to monitor, anticipate and rapidly
correct perturbations can help maintain
stability
Patient self management contributes to
optimization in these complex patients
Thank You