Chronic kidney disease

Question 1

What are the goals of treatment in CKD

Answer 1

Minimizing the progression of the disease
- treatment of proteinuria
- treatment of hypertension
- management of secondary hyperparathyroidism

Avoiding further renal damage
- specific therapy for the primary disease (often not available)

Management of any comorbidities

Management of consequences of CKD
- Anemia (non-regenerative)
- Arterial hypertension
- dehydration
- hyperphosphatemia
- hypokalemia ….

Question 2

What factors influence progression of CKD

Answer 2

CKD is a progressive disease due to the following limited renal responses to injury

Factors influencing progression are:
- intraglomerular hypertension
- glomerular hypertrophy
- hypertension
- proteinuria

Question 3

Explain the physiopathology of CKD progression

Answer 3

When part of the renal mass is lost, compensatory hypertrophy and intra-glomerular hypertension occur in the remaining nephrons resulting in an increase in single nephron GFR
- this adaptative process maintains GFR

These mechanisms result in cell damage and progression of the disease

Arterial hypertension may cause proteinuria which causes further damage, and glomerular damage

Question 4

Explain why proteinuria is a strong, independent risk factor for progression of CKD

Answer 4

Increased protein in the glomerular filtrate injures tubular cells as they are overwhelmed with proteins
- this triggers activation of inflammatory mediators and vasoactive substances via gene up-regulation

This chronic inflammation and damage ultimately result in renal tubular fibrosis, interstitial fibrosis and loss of nephrons

Question 5

Aside proteinuria, can you give another important factor of progression of CKD

Answer 5

Restriction of phosphate in cats with CKD results in longer survival, so either increased phosphate or hyperparathyroidism may play a role in CKD progression

Question 6

Explain why dietary management is important in CKD

Answer 6

Multiple studies demonstrates the benefit in terms of survival and amelioration of clinical signs when cats with CKD are fed a “renal diet”

Important factors in dietary management include:
- Phosphate resriction is much more important than protein restriction
- Cats are dependent on protein in their diet and protein restriction will result in muscle catabolism
- Lower protein diets are often not as palatable and these cats need to eat

Never prioritize a renal diet over nutrition
- If the cat refuse a renal diet then allow it to eat other food
- they need calories or they will catabolize their own muscles to provide protein

Question 7

What ideally are the components of a renal diet

Answer 7

Reduced phosphate
Reduced (but high quality) protein
Reduced sodium
Increased B vitamins
Increased caloric density
Polyunsaturated fatty acids
Increased potassium
Reduced acidifying effet
Antioxydants

Question 8

How would you characterise the anemia seen in CKD

Answer 8

The anemia of CKD is normocytic, normochromic and non-regenerative

Anemia in cats with CKd probably contributes to lethargy, inappetence, weakness and weight loss

Question 9

What is the cause of the anemia in CKD

Answer 9

The anemia is typically caused by reduced erythropoeitin production by the diseased kidneys

Question 10

When is rHuEPO therapy indicated

Answer 10

rHuEPO therapy is usually reserved for cats with moderate to severe, clinically significant anemia (PCV < 15%)

Question 11

Explain how iron deficiency can contribute to the anemia and how to prevent it

Answer 11

Iron deficiency can contribute to the anemia through inadequate dietary intake and gastro-intestinal blood loss

If gastro-intestinal bleeding occurs, this requires the use of sucralfate and/or H2 receptor antagonists

Ferrous suplhate injection may be needed
- Iron dextran 50 mg/cat, IM every 3-4 weeks

Question 12

What are the main side effects of rHuEPO therapy

Answer 12

Hypertension

Polycythemia

Induction of anti-rHuEPO antibodies
- thought to occur in 30% of treated cats

Question 13

Explain why darbepoetin is currently preferred to rHuEPO and how is it used

Answer 13

Darbepoetin is thought to be less immunogenic than rHuEPO

Induction phase:
- 1µg/kg SC once weekly until the target PCV is reached (35-40%)

Maintenance phase:
- once the target range is met, the dosing interval is changed to once every 2 to 3 weeks with continuing titration

Question 14

Where is erythropoietin mainly produced

Answer 14

EPO is mainly produced in the peritubular interstitial cells of the inner renal cortex and outer medulla in the kidney

Question 15

What is the main stimulus for erythrpoietin synthesis

Answer 15

The main stimulus for EPO synthesis is renal hypoxia
- when hypoxia is present, degradation of hypoxia-inducible factor 1 (HIF-1alpha) is inhibited
- HIF-1alpha is free to bind to intracellular elements and stimulate EPO gene to increase EPO production
- EPO will bind to its receptor expressed on the surface of erythroid progenitor cells and leads to increased erythropoiesis

Question 16

Give a definition of anemia

Answer 16

Anemia is defined as a state of deficient mass of circulating RBCs and hemoglobin, which results in reduced oxygen delivery to all organs and a subsequent decline in cell metabolism

Question 17

List some of the adaptative response mechanisms accompanying anemia

Answer 17

Adaptative mechanisms include increased release of:
- plasma norepinephrine
- renin
- angiotensin II
- aldosterone

As anemia becomes more severe, cats may also develop left heart enlargement secondarily to hemodynamic compensation, and become more prone to congestive heart failure

Question 18

Explain the pathogenesis of anemia of renal disease

Answer 18

Anemia of renal disease is multifactorial:

- Decreased erythropoiesis (i.e., lack of EPO, inflammatory cytokines, iron deficiency (absolute or relative), uremic toxins)

- Shortened RBC survival (e.g., uremic toxins, low-grade hemolysis, premature removal by reticuloendothelial cells)

- Increased RBC loss (e.g., thrombocytopathy, gastrointestinal ulcers)

Question 19

What is the role of hepcidin in iron metabolism

Answer 19

Hepcidin is produced by the liver in response to inflammation and iron loading, and is suppressed by normal eryhtropoietic activity and iron deficiency

Hepcidin is considered to be the central regulator of systemic iron homeostasis
- the primary inflammatory mediator causing its increased production is interleukin-6

Hepcidin’s biological actions are mediated by its binding to and internalization of ferroportin

The decrease in enteral absorption (at the duodenum level) and the sequestration of iron in macrophages eventually leads to anemia by decreasing availability of iron for hemoglobin production

Hepcidin concentrations are increased in CKD patients in part due to decreased renal clearance

Question 20

Explain why proteinuria in cats with CKD has been shown to be predictive of survival

Answer 20

Proteinuria is an independent factor

Even UPCs of 0.2-0.4 have a significant effect on survival compared to UPCs of < 0.2

Question 21

What are the effect of ACE inhibitors and how to they act on renal vascularisation

Answer 21

ACE inhibitors are anti-proteinuric and have beneficial hemodynamic effects
- They have a selectively greater vasodilation of the efferent glomerular arteriole compared with the afferent arteriole
- This results in sustained GFR through increased glomerular blood flow but with reduced intraglomerular pressure and thus reduced proteinuria

Question 22

What are the indications and contra-indications of ACE inhibitors

Answer 22

Indications:
- cats with UPC > 0.4
- Cats with hypertension and proteinuria
- Cats with hypertension not adequately controlled with amlodipine

Contra-indications:
- Dehydration
- Hypovolemia
- Hyperkalemia
- Cats suffering acute deterioration in renal function

Question 23

What is the most common cause of hypertension in cats

Answer 23

CKD is the most common cause of hypertension in cats
- Approximately 20-30% of cats with CKD are hypertensive

Question 24

Explain why hypertension should be managed in a CKD cat

Answer 24

Hypertension should be managed due to:
- clinical effects on target organs
- possible effect on progression (perhaps via proteinuria)

Question 25

What is the treatment of choice for hypertension in cats

Answer 25

The treatment of choice is amlodipine

Amlodipine is a calcium channel inhibitor inducing arterial vasodilation

The dose is 0.625-1.25 mg/cat/day

Question 26

What is the place of ACE inhibitors in the management of hypertension

Answer 26

Alone ACE inhibitors are unlikely to control hypertension
- they may provide additional blood pressure control with amlodipine

Should be used concurrently to amlodipine if the cat is proteinuric

Question 27

Explain the different forms of phosphate found in the body

Answer 27

Approximately 85 % of the body’s phosphate is located as hydroxyapatite in bone

14% are located intracellularly or as key biomolecules (e.g., DNA, RNA, ATP, …)
- phosphate is the most abundant cellular anion

Only 1% of the body’s phosphate is located extracellularly
- 2/3 as organic phosphate
- 1/3 as inorganic form (e.g., H3PO4) that is measured by laboratory analysers

Question 28

What are the three main organ systems that regulate phoosphate levels

Answer 28

The three main organ systems that regulate phosphate levels are:
1/ Intestine
- active duodenal absorption under the influence of calcitriol
- PTH also indirectly increases intestinal absorption of phosphorus via stimulating 1-alpha-hydroxylase activity and calcitriol production

2/ Bone
    - calcium and phosphorus are released via PTH and calcitriol stimulation of osteoclastic activity

3/ Kidney
- modulation of phosphate reabsorption and excretion in the tubules

Question 29

What causes hyperphosphatemia of CKD

Answer 29

The main issue in CKD is loss of excretory capacity in the proximal tubule

Free and complexed inorganic phosphate ions are filtered by the glomeruli and normally up to 95% is reabsorbed in the proximal tubule
- this varies with serum phosphate levels
- it is also dependent on GFR

Expression of the sodium-phosphate co-transporter in the proximal tubule is influenced by intestinal phosphate, PTH and phosphatonins ((e.g. FGF-23)

Loss of functional mass leads to impaired excretion of phosphate via the kidneys
- increased phosphate levels result in a reduction of serum ionized calcium, which then leads to an increase in serum PTH levels
- this chronic increase increase in PTH levels is termed “renal secondary hyperparathyroidism”

Question 30

What is FGF-23

Answer 30

FGF-23 is produced by osteoblasts and osteocytes

FGF-23 is responsible for the down-regulation of expression of the sodium-phosphate co-transporter in the proximal tubule
- this results in increased phosphate excretion

FGF-23 also inhibits 1-alpha-hydroxylase and reduces calcitriol production

FGF-23 down-regulates the production of PTH

Question 31

Explain why reduction of hyperphosphatemia is very important in the management of CKD

Answer 31

Studies demonstrate that hyperphosphatemia and elevated PTH are common in CKD

The suggestion that PTH elevations contribute to the pathogenesis and clinical signs of CKD is widely accepted
- renal secondary hyperparathyroidism is common in cats with higher stages of CKD
- control of phosphate and therefore PTH is likely to prolong survival in cats with CKD
- Serum phosphate levels are significantly associated with survival

Question 32

How could you lower serum phosphate levels

Answer 32

The phosphate restriction should initially take the form of a renal diet

In later stages of CKD or severely elevated phosphate, intestinal phosphate binders may be required
- they are required if the cats will not eat renal diets

The goal is to maintain serum phosphate at the low end of the reference range
- ideally less than 1.5 mmol/l (<4.5 mg/dl)

It can take 2-3 months for the serum phosphate level to stabilize

Question 33

Explain how intestinal phosphate binders work and give some exemples

Answer 33

Intestinal phosphate binders reduce the amouunt of phosphorus absorbed from the intestine by physically binding to dietary phosphorus to form insoluble ions, which are then excreted in the feces
- All of the phosphate binders have the potential to decrease the absorption of other drugs therefore it is advised to separate drugs by at least 2 hours

Aluminium salts:
- palatability can be an issue in cats
- aluminium toxicity has been reported in dogs but is unlikely to be an issue in cats
- sucralfate is ineffective
- the dose is 30-90 mg/kg a day in divided doses and mixed with each meal

Calcium salts
- Hypercalcemia (and then soft tissue mineralization) due to high Ca*PO4 product) can be a problem
- Suppreesion of PTH due to increased calcium and bone mineral breakdown can also be a problem
- Ipakitine is used successfully in many patients
- the dose is 30-90 mg/kg/day in divided doses

Lanthanum salts

Question 34

What are the main causes of hypokalemia in CKD cats

Answer 34

Inappropriate kaliuresis

Reduced intake due to hyporexia

Question 35

What are the typical clinical signs of hypokalemia

Answer 35

Overt clinical signs of hypokalemia are generally not seen until the serum concentration falls below 3.0 mmol/L

Signs typically include:
- generalized skeletal muscular weakness which is classically manifested as a plantigrade stance on the hind limbs, and ventroflexion of the neck
- other signs include a stiff, stilted gait and a wide based stance
- chronic and severe hypokalemia causes muscle fiber hypopolarisation, leading to extreme muscle weakness and eventual rhabdomyolysis (this can be accompanied by elevations of serum creatinine kinase levels)

Myocardial contractility is also reduced by hypokalemia (cardiac output falls, arrhythmias may occur due to disturbed myocardial membrane potentials)
- changes on ECG include:
- decreased T-wave amplitude
- S-T segment depression
- supra-ventricular and ventricular arrhythmias

Question 36

Hypokalemic polymyopathy is considered the commonest cause of generalized muscle weakness in cats. Can you give other significant consequences of hypokalemia that are of particular importance in cats with CKD

Answer 36

Hypokalemia can directly contribute to renal damage (hypokalemic nephropathy)
- it can contribute to advancement of renal failure
- the main physiopathological mechanisms explaining that consequence on renal failure are:
- hypokalemia-induced renal vasoconstriction
- reduced responsiveness of the kidneys to vasopressin
- increased renal ammoniagenesis which directly contributes to interstitial nephritis

Hypokalemia will contribute to both the metabolic acidosis and hypertension that can occur in CKD

Hypokalemia will contribute to inappetence and anorexia commonly seen in the uremic syndrome

Even small reductions in serum potassium concentrations may have the ability to adversely affect renal function and the clinical well-being of cats in CKD, even in the absence of polymyopathy

Question 37

How can you treat hypokalemia

Answer 37

Non-acidifying, low-proteins diets replete in potassium will help to maintain serum potassium concentrations

Potassium concentrations should be monitored regularly in cats with CKD and if they fall below 4 mmol/l, supplementation with potassium salts is recommended
- potassium gluconate is preferable to potassium chloride which is unpalatable and may cause gastrointestinal irritation
- initial doses of 1-4 mmol K+ twice daily may be given with food

Question 38

Why is it important to control metabolic acidosis in CKD

Answer 38

Metabolic acidosis is frequently encountered in CKD

It may contribute to anorexia, vomiting, nausea, weight loss, lethargy, hypokalemia and skeletal demineralization

Significant metabolic acidosis generally does not occur until late in the disease

Question 39

How can you explain that CKD cats are more prone to urinary tract infections

Answer 39

UTI are common in cats with CKD (22% cats with CKD might have a UTI)

Loss of urinary concentrating ability in CKD favor UTI

Question 40

What important points regarding UTIs in cats with CKD you could give

Answer 40

Female cats may be predisposed

They often show no clinical signs

E. coli is the most common bacteria involved
- the majority of E. coli isolates are susceptible to amoxy/clav

Re-infection/recurrence is common
- if recurrence occurs, imaging may be advisable to ensure no uroliths or other abnormality is present and causing a focus of infection

The sediment is usually but not always active

Question 41

Give factors affecting survival in CKD

Answer 41

Stage of CKD
- the higher the stage the shorter the survival time

Proteinuria
- the UPC is strongly related to survival in cats
- cats with a UPC > 0.4 had a 5 fold higher risk of reaching a renal end point than cats with a UPC < 0.2

Hypertension
- hypertension is associated with increased UPC and therefore is not an independent risk factor for death in cats with CKD

Hyperphosphatemia
- it is not an independent factor (correlated with creatinine)
- it is predictive of survival in multivariate analysis

Anemia
- it is not an independent factor
- low hematocrit has been associated with shorter survival

Weight loss