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An overview of the management of

chronic kidney disease in dogs and


cats?

Mark Dunning

School of Veterinary Medicine and Science

What is chronic kidney disease?


Defined as the presence of structural or functional kidney disease in
one or both kidneys that has been present for an extended period.
Disease present for 3 months or more may be considered as chronic
Thus the definition is relatively all encompassing
Minor structural defect
Major loss of structural integrity
The combination of clinical history and examination findings and
diagnostic test and therapies will therefore vary greatly between
patients.
Thus the old definition of CRF comes under the heading of CKD but
is not as all encompassing

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What is chronic kidney disease?


In order to manage CKD we need to be able to stage the condition
Until relatively recently the degree of kidney disease was considered
in a subjective way:
Normal renal function
Early renal disease: No biochemical evidence.
Renal insufficiency: No azotaemia, decreased GFR; poor
concentrating ability.
Early renal failure: Mild azotaemia, Mal-adaptions can lead to
hyperparathyroidism and hypokalaemia.
Uraemic renal failure: Moderate to severe azotaemia. Systemic
signs present: e.g. bone pain, uraemic gastritis, anaemia, metabolic
acidosis.
End-stage renal failure: Increasing risk of systemic clinical signs
and uraemic crisis.

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How do we characterise chronic


kidney disease?
Recent classification from the international renal interest society
(IRIS) (combination of USA and European experts)
This system enables enables planning of therapy and provision of a
prognosis all important for owners
This is a 4 stage system with sub-categories:
Stages are defined by creatinine concentration

This is measured after a the animal has been fasted


The patient should be well hydrated
Measured on at least 2 occasions

Further characterisation by the magnitude of proteinuria


Determined by the UPC ratio

Should ensure that the sediment is inactive


Need to measure the value on 2-3 samples taken over a period of 2 weeks
The significance of a given alteration in UPC depends on the IRIS stage
This relates to the sieve principle

Further characterisation by the arterial blood pressure


As with UPC need to average over a period of a few weeks

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What is the IRIS system?

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What is the IRIS system?

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What is the IRIS system?

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What is the MDB in making the


diagnosis of CKD?
Same old chestnuts are important when screening for
CKD

Urea
Creatinine
Phosphate
(acid-base status)
(potassium)
Urinalysis you cannot investigate renal disease without a urine
sample

Loss of concentrating function will be seen at around 66% loss of


nephrons BUT
The development of azotaemia will be seen at around 75% loss of
nephrons

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What is new in the diagnosis of


CKD?
Fractional clearance of molecules
Urine NAG and RBP

Recent studies looking into determining whether this markers enable determination of CKD
Some evidence for increased concentration of urine RBP as indicator of tubular damage
Mounting evidence that NAG is suggestive of tubular pathology as this is present in lysosyme granules
of the proximal tubule
Both of these markers was found to be elevated in aged dogs with CKD

Creatinine normal ranges (vs IRIS scale)


Mounting evidence that there is breed variation
Large dogs often have higher concentrations

Studies have reported ranges of between 106 micromol/l in very


small dogs to 133 micromol/l in large and very large dogs
Important to realise that creatinine conc will vary with diet and body mass change

This must be factored into temporal evaluation of creatinine conc

School of Veterinary Medicine and Science

What is new in the diagnosis of


CKD?
Fractional clearance of molecules
Urine NAG and RBP

Recent studies looking into determining whether this markers enable determination of CKD
Some evidence for increased concentration of urine RBP as indicator of tubular damage
Mounting evidence that NAG is suggestive of tubular pathology as this is present in lysosyme granules
of the proximal tubule
Both of these markers was found to be elevated in aged dogs with CKD

Creatinine normal ranges (vs IRIS scale)


Mounting evidence that there is breed variation
Large dogs often have higher concentrations

Studies have reported ranges of between 106 micromol/l in very


small dogs to 133 micromol/l in large and very large dogs
Important to realise that creatinine conc will vary with diet and body mass change

This must be factored into temporal evaluation of creatinine conc

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At what point should we quantify


renal function?
GFR is the value that best quantifies renal function
But when is it valuable to measure GFR?

Before the onset of azotaemia

In cases of non-azotaemic PD/PU or familial renal disease

To determine absolute degree of renal function when disparity between creatinine and urea
concentrations
To determine progression in renal disease over time
To calculate appropriate reduction in drug dose in a given patient

Important if drug cleared by kidneys

What methods are available


Inulin clearance gold standard
Iohexol used with increasing frequency in small animals (samples can be sent
to RVC and Michigan)
Creatinine clearance (endogenous vs exogenous) source of creatinine
Radio-isotope studies limited practicality

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What are we trying to achieve in


treating in CKD?
Identify and treat underlying diseases (e.g.
pyelonephritis, urinary obstruction)
CKD therapy is aimed at preventing or treating complications of
reduced renal function
Initially must manage co-morbid conditions associated with the
uraemic syndrome
Need to address the chronic medical therapy
Maintaining hydration, electrolyte balance, nutritional status

Slow down the functional decline


Monitor for alteration in clinical condition CKD highly changeable
disease
Owner vigilance
On-going monitoring schedule often individualised for each patient

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What are we trying to treat in CKD?


A number of complications develop secondary to CKD
These all require effective therapy to slow the decline
of patients with CKD

Hyperphosphataemia*
Metabolic acidosis*
Hyperparathyroidism*
Hypertension
Hypokalaemia
Proteinuria(*)
Uraemic GI disease
Anaemia*
Anorexia
Weight loss
Dehydration*

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What is the value of a renal diet?


This is not limited to reduced protein concentration and
so standard senior diets are not equal in efficacy
Additional and possibly more important aspects include

Reduced phosphate and sodium content


Increased soluble fibre concentration
Increased B vitamin concentration
Increased concentration of anti-oxidants and O3FA
Neutralising effect on acid-base
Feline diets are also supplemented with potassium

If the BCS is not being maintained then re-evaluation for uraemic


complications should be undertaken, e.g. development of a UTI
If appropriate alimentation is not achieved orally then consider PEG tube
placement

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What is the significance of acidosis


in CKD?
Metabolic acidosis occurs frequently in stage III
and IV CKD patients
This leads to impaired anabolism and impaired
protein nutrition
A reduction in appetite and overt weight loss may be
seen
Supplementation in humans has been reported to
slow progression in CKD and improve nutritional
status

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What is the significance of acidosis


in CKD?
When HCO3- concentration falls below
18mmol/l in dogs and 16 mmol/l in cats therapy should be considered
<10% of stage II and III cats will be acidotic, whereas 50% of cats with overt uraemia
will be acidotic
iSTAT measurement EC8/CG4/8 are suitable in clinic analysers
Difficult to accurately measure this on external lab samples

Initial step is to introduce a renal diet, this is designed to maintain a pH


neutral state
Should this not normalise HCO3- then introduction of an alkaliniser
should be considered
NaHCO3- and KCl are most commonly used
KCl has advantage in cats of supplementing potassium as well as alkalinisation

Dose of between 40-60mg/kg 8-12 hourly

NaHCO3- is poorly absorbed from GIT but can be effective

Dose of between 8-12mg/kg 8-12 hourly

Efficacy assessed after 10-14 days on medication


Blood gas to assess efficacy
Cannot assess efficacy of therapy on urine pH (too many variables influencing urine
pH)

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Why is it important to manage


hyperphosphataemia?
Retention of phosphate occurs early in renal disease
Increased excretion normalises plasma concentration
This occurs via combined effects of FGF-23 and PTH increasing
phosphaturia
Although initially able to normalise concentration, over time this
mechanism fails and the phosphate begins to climb once again
Over time this leads to sustained elevation in PTH and reduced
production of vitamin D
In animals with stage 3 and 4 disease the compensatory
mechanisms fail and phosphate rises uncontrollably
This leads to renal secondary hyperparathyroidism and ultimate
progression in CKD
Recent studies have shown early increase in PTH prior to
hyperphosphataemia
Measurement of PTH should be discussed with the owners of all animals
with clinical signs of CKD and PD/PU

This significantly affects mortality in CKD


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Why is it important to manage


hyperphosphataemia?
Initial control may be based on diet alone
Target phosphate ranges should be below the URR of most labs
May be sufficient to maintain normal phosphate up to stage 3
If this is not sufficient after 3-4 weeks then alternative sources
are required

Control of phosphate via aluminium hydroxide

Important to use on food not between meals


Has been reported as being neurotoxic in humans, single report in veterinary literature
Licensed products available for cats (lanthanide) effective but expensive
Care with alternatives such as calcium salts and these may lead to hyperclacaemia

Particularly if used with calcitriol

Other considerations would be sevelamer hydrochloride


human studies suggest lanthanides are superior to sevelamer

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What is the value of calcitriol?


Patients with CKD have reduced concentrations of
calcitriol

Renal secondary hyperparathyroidism


Reduced activity of 1 alpha-hydroxylase

Initial approaches to ameliorate the reduction in calcitriol can be met by


reducing phosphate intake
As the disease progresses this becomes less effective in maintaining
normal concentrations
Major drive for supplementing calcitriol is to reduce PTH concentrations and
improve mineral metabolism

More recent studies in humans have shown additional benefits

Suppression of activity of RAAS


Upregulation of vitamin D receptors
Reducing podocyte loss associated with glomerular hypertrophy

These benefits have been recognised to aid with limiting progression in CKD and improving
survival

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What is the value of calcitriol?


Evidence suggests of some value in dogs with stage 3 and 4
disease

May have value in staged 1 and 2 though yet to be proven

At present studies have not shown a benefit in cats, although limited literature on
subject

Recent studies have shown very early elevation in PTH and thus is such cases there may be an argument for
introduction of calcitriol

Currently well tolerated at the doses evaluated

In initiating therapy important target must be achieved and maintained

Need to ensure normal phosphate concentration


Ionised calcium must be within normal limits

Total calcium concentration does not accurately predict ionised concentrations and thus should not be used

If these conditions are not met, or change during therapy calcitriol may promote soft tissue mineralisation
If hypercalcaemia develops then the dose should be altered to every other day dosing at twice the previous
daily concentration
Measurement of PTH and possibly vitamin D
Monitoring should be every 2-4 weeks at beginning and then every 3-6 months once stable

School of Veterinary Medicine and Science

What is the value of calcitriol?


In choosing vitamin D supplementation best to
choose most active form as precursors require renal
activation
This step is lacking in CKD and is partly responsible for the
predicament in the first place.
Most commonly used product in the UK is 1-Alpha (alphacalcidol), easiest
formulation to use is liquid (2mcg/ml)
Rapid onset, as little as 6 hours in some studies
But this is difficult to dose accurately, as a single drop accounts for 100ng.
As a result for many patients this needs to be compounded

USA source is most valuable


Starting dose of 2-2.5ng/kg PO SID
UK sources make dosing for anything smaller than a mastiff difficult!
Drug reformulation is easiest method of dosing
USA compounders will do this and ship to UK

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What else can control secondary


HPTH?
PTH receptor antagonists

Cinacalcet human drug been around for a while


Shown to reduce complications of secondary HPTH
Care as need to be vigilant for signs of hyperphosphatamia and hypocalcaemia
Not readily available as very expensive and doses not clarified for cats or dogs at present

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Why is it important to maintain


hydration?
Maintenance of hydration is dependent on the patient consuming
sufficient water on a daily basis
often not possible, sleeping/out door activity, anorexia, vomiting, fluid losses
e.g. diarrhoea

May be more notable in cats than dogs with CKD, possibly due to longer
periods of time asleep
More frequent episodes of dehydration leads to more intermittent
exacerbations in acute on chronic disease. This will lead to a more
rapid progression in disease
Dehydration is more likely to lead to lethargy, anorexia, constipation, all
of which increase the risk of developing acute on chronic kidney injury
and also negatively impact on quality of life

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Why is it important to maintain


hydration?
When do you supplement fluids

Individual case basis particularly useful when you know the azotaemia responds to IVFT

Sieve analogy

Body weight is a good measure of hydration and can be used to determine the need to
supplement
Cats may be easier to treat than dogs via SC route

Routes, volumes and frequency


Largely empirical at present

Often administered every 1-3 days


Volume is dependent on tolerance, for cats often recommend 75-100ml per dose
Can determine appropriate amount for maintenance and supplement difference

Caution in these situations as excessive NA intake may impair efficacy of anti-hypertensive therapy and renal
perfusion

SC route most commonly chosen via IV catheter and standard giving set
Can also use surgically placed button/cannula
Due to complications and poor tolerance of SC route, consider PEG tube placement for
home fluids is reasonable

This enables pure water intake preventing electrolyte dyscrasias often seen
with admin of LRS and Saline
Can also enable feeding of patients to maintain calorific intake
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Whats new in the management of


CKD?
Mineralocorticoid antagonists
Some suggestion that up-regulation and activation of mineralocortiod receptors
(MR) plays role in progression of CKD.
The beneficial effects of the MR antagonists are independent of the hypertensive
effect of aldosterone, indicating that blocking the activation of the MR may have
unique clinical importance
They may influence kidney cells such as mesangial cells, podocytes, and renal
fibroblasts
Peer reviewed efficacy in dogs and cats is yet to appear however this may well be a valuable
consideration in long term management

Orally administered micro capsules

Micro-capsules containing yeast molecules are under investigation

Micro-capsules containing bacteria or engineered cells

Experimental work suggests urea concentration is reduced when administered


Further work necessary to clarify clinical benefit as no obvious effect on stage of disease
Urea diffuses into the microparticles by diffusion

Limited literature in cats or dogs

Recent publication suggested no benefit of azodyl (symbiotic product from Vetoquinol)


But not used according to manufacturers recommendations therefore jury still out

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Whats new in the management of


CKD?
ACE inhibitors and angiotensin blockers
The weight of evidence is for use in the management of proteinuria
Studies in humans have shown that ACE inhibition lowers systemic blood
pressure, lowers glomerular capillary pressure, prevents glomerular hypertrophy
Feline studies have shown improvement in the degree of proteinuria but there is
limited evidence of improved survival in non-proteinuric animals
In dogs there is a little more evidence of a survival beneficial outside of that
associated with proteinuria
The influence of diet in these studies have not been interpreted clearly however

Angiotensin blockers new but evolving in management of proteinuria in cats Semintra


https://www.boehringer-ingelheim.com/news/news_releases/press_releases/
2013/02_september_2013animalhealth.html

Important to monitor changes in creatinine concentration when


initiating ACE inhibitor therapy
Never use in clinically dehydrated animal or one showing signs of hypovolaemia
Monitor creatinine concentration before and 48-72 hours after initiating therapy
Changes >40-50micromoles/l or progressive increase in creatinine concentration
should prompt reassessment of therapy
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Whats new in the management of


CKD?
Anti-oxidants
A small number if studies looking into oxidative stress in CKD have
shown benefit in reducing serum creatinine concentration
Studies have also shown a reduction in the degree of proteinuria,
interstitial fibrosis and glomerulosclerosis
Renal diet should be sufficient to replace these as these are
supplemented
Optimum dose at present not determined for effective therapy

O3FAs
Evidence for reduction of cholesterol, reduce inflammation, inhibit
coagulation, improve intra-renal haemodynamics and limit intra-renal
calcification
Dogs provided with omega 3 FA showed reduced mortality, slower
progression in their renal disease (histological assessment), less
proteinuria and lower cholesterol concentrations
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Whats new in the management of


CKD?
We must be able to use stem cells?!
Recent study looking into intrarenal injection of bone marrow and adipose tissue
derived mesenchymal stem cells
Injection procedure did not lead to deterioration in renal function
No significant improvement in GFR seen (study quotes modest
improvement)
Difficult as been investigated in humans for ischaemic/acute renal injury
So CKD is not an appropriate disease model to use
Benefits may be due to the modification in cytokine environment as
cytoarchitecture was similar in experimental groups despite serological
differences

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SO.what is the prognosis?


Dogs with stage 3 and 4 disease tend to be
progressive
Ultimate rate of progression depends heavily on confounding factors
Survival ranges of months to a year depending on severity of disease at outset
Presence of negative prognostic indicators: proteinuria, hypertension reduces
survival time

Cats with CKD tend to progress more slowly than dogs


Proteinuria is a negative prognostic indicator

Sadly despite the classification system the highly volatile nature of


CKD due to multiple factors that influence stability means it is often
difficult to provide owners with an accurate prognosis.
Most appropriate method to maintain good health is to monitor these
patients frequently to pick up on the various metabolic
derangements that can occur
Effect of NSAIDs?
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SO.how frequently should I


monitor these patients?
Approximate guidelines only however
Suggested monitoring frequency for stage I and II animals is every 4-6 months
Suggested monitoring frequency for stage III and IV animals is every 3-4 months
This frequency will vary depending on the presence of stable/changeable clinical
signs

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