Chronic kidney disease Flashcards
Medical management of CKD
What are the goals of treatment in CKD
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 ….
What factors influence progression of CKD
CKD is a progressive disease due to the following limited renal responses to injury
Factors influencing progression are:
- intraglomerular hypertension
- glomerular hypertrophy
- hypertension
- proteinuria
Explain the physiopathology of CKD progression
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
Explain why proteinuria is a strong, independent risk factor for progression of CKD
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
Aside proteinuria, can you give another important factor of progression of CKD
Restriction of phosphate in cats with CKD results in longer survival, so either increased phosphate or hyperparathyroidism may play a role in CKD progression
Explain why dietary management is important in CKD
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
What ideally are the components of a renal diet
Reduced phosphate
Reduced (but high quality) protein
Reduced sodium
Increased B vitamins
Increased caloric density
Polyunsaturated fatty acids
Increased potassium
Reduced acidifying effet
Antioxydants
How would you characterise the anemia seen in CKD
The anemia of CKD is normocytic, normochromic and non-regenerative
Anemia in cats with CKd probably contributes to lethargy, inappetence, weakness and weight loss
What is the cause of the anemia in CKD
The anemia is typically caused by reduced erythropoeitin production by the diseased kidneys
When is rHuEPO therapy indicated
rHuEPO therapy is usually reserved for cats with moderate to severe, clinically significant anemia (PCV < 15%)
Explain how iron deficiency can contribute to the anemia and how to prevent it
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
What are the main side effects of rHuEPO therapy
Hypertension
Polycythemia
Induction of anti-rHuEPO antibodies
- thought to occur in 30% of treated cats
Explain why darbepoetin is currently preferred to rHuEPO and how is it used
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
Where is erythropoietin mainly produced
EPO is mainly produced in the peritubular interstitial cells of the inner renal cortex and outer medulla in the kidney
What is the main stimulus for erythrpoietin synthesis
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
Give a definition of anemia
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
List some of the adaptative response mechanisms accompanying anemia
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
Explain the pathogenesis of anemia of renal disease
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)
What is the role of hepcidin in iron metabolism
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
Explain why proteinuria in cats with CKD has been shown to be predictive of survival
Proteinuria is an independent factor
Even UPCs of 0.2-0.4 have a significant effect on survival compared to UPCs of < 0.2
What are the effect of ACE inhibitors and how to they act on renal vascularisation
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
What are the indications and contra-indications of ACE inhibitors
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
What is the most common cause of hypertension in cats
CKD is the most common cause of hypertension in cats
- Approximately 20-30% of cats with CKD are hypertensive
Explain why hypertension should be managed in a CKD cat
Hypertension should be managed due to:
- clinical effects on target organs
- possible effect on progression (perhaps via proteinuria)
What is the treatment of choice for hypertension in cats
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
What is the place of ACE inhibitors in the management of hypertension
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
Explain the different forms of phosphate found in the body
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
What are the three main organ systems that regulate phoosphate levels
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
What causes hyperphosphatemia of CKD
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”
What is FGF-23
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
Explain why reduction of hyperphosphatemia is very important in the management of CKD
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
How could you lower serum phosphate levels
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
Explain how intestinal phosphate binders work and give some exemples
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
What are the main causes of hypokalemia in CKD cats
Inappropriate kaliuresis
Reduced intake due to hyporexia
What are the typical clinical signs of hypokalemia
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
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
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
How can you treat hypokalemia
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
Why is it important to control metabolic acidosis in CKD
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
How can you explain that CKD cats are more prone to urinary tract infections
UTI are common in cats with CKD (22% cats with CKD might have a UTI)
Loss of urinary concentrating ability in CKD favor UTI
What important points regarding UTIs in cats with CKD you could give
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
Give factors affecting survival in CKD
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
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