CKD Flashcards
What is the “trade off hypothesis” and how does it lead to spontaneous progression of CKD?
The renal adaptive processes that maximize kidney function to sustain homeostasis result in ongoing damage to the surviving nephrons. Therefore, CKD can progress even if the initial disease process or insult is cured
What is the prevalence of CKD in canine and feline populations?
Feline: 1-3% of US cats
Canine: 0.5-1.5% of US dogs
For serum creatinine to increase, what percent of kidney function must be lost?
75% of function in both kidneys
Why do kidneys become smaller with CKD?
Functioning nephrons are replaced by scar tissue and chronic inflammation
The majority of cats (70%) and dogs (60%) with CKD display what histopathologic changes in renal biopsy?
Tubulointerstitial nephritis
What is the MST of cats with IRIS Stage II CKD? Stage III? Stage IV?
Stage II: 1,151 days
Stage III: 679 days
Stage IV: 35 days :(
What factors influenced survival time in cats with CKD?
IRIS stage, serum phosphorus, severity of proteinuria
In all dogs with CKD, what was the MST? Dogs with IRIS Stage III and IV had how many times greater risk of mortality?
226 days
Stage III = 2.6 times the mortality
Stage IV = 4.7 times the mortality
What factors are associated with prognosis in dogs with CKD?
Proteinuria, hypertension, BUN, lower body condition score do worse
What are the histopathologic changes that accompany uremic gastritis in dogs?
Mineralization of mucosal and submucosal blood vessels, edema, glandular atrophy
What gastric hormone is increased in CKD due reduced renal clearance?
Gastrin - however, increased gastric pH typically does not occur in CKD patients
What are the clinical signs of uremic stomatitis?
- Dry mucous membranes (xerostomia)
- Oral ulcerations: usually buccal mucosa and tongue
- Brown discoloration of the dorsal surface of the tongue
- Sloughing and necrosis of the anterior portion of the tongue from arteritis
- Urine smelling breath
What factors contribute to the decreased urine concentrating ability observed in CKD?
- Increased solute load per surviving nephron => solute diuresis
- Disruption of the renal medullary architecture => disruption of the counter current multiplier system
- Impaired renal responsiveness to ADH
Why might the kidneys develop impaired responsiveness to ADH?
- May be due to an increase in distal renal tubular flow rate, which limits equilibrium of the tubular fluid with the hypertonic medullary interstitium
- Uremia may also impair ADH-stimulated adenyl cyclase
As urine concentrating ability is lost, what determines urine volume?
Daily urine solute load - sodium and urea
- Can modify the diet to alter this
What are the major mechanisms that contribute to hypertension in CKD?
- Fluid retention
- Activation of RAAS
- Increased activity of the sympathetic nervous system
What transcription factor regulates EPO synthesis in the kidneys?
Hypoxia inducible factors, especially HIF-2
What percent of asymptomatic cats with CKD have evidence of renal secondary hyperparathyroidism? What is the overall prevalence in all CKD cats?
47% of asymptomatic cats
84% of all CKD cats
What is urea synthesized from?
Synthesized using nitrogen derived from amino acid catabolism
What is urea metabolized to?
Ammonia and amino acids + CO2
Hyperphosphatemia occurs when GFR declines below what percent of normal?
Below 20% of normal
Why might total calcium increase but ionized calcium decrease in CKD?
Increased calcium binding to organic acids (citrate, PO4, sulfate) that are not being excreted due to CKD
What may the cause of hypokalemia in cats with CKD?
- Decreased dietary sodium may activate RAAS and promote kaliuresis => hypokalemia
- Decreased food intake
What are the consequences of hypokalemia in CKD cats?
- Anorexia
- Muscle weakness
- Worsening kidney function (reversible, functional decline in GFR) - improved with K supplementation
What RAAS system abnormalities have been identified in CKD cats?
Low plasma renin, but high plasma aldosterone concentrations
How is SDMA formed in the body?
The process of protein degradation includes methylation of arginine into various substances, including symmetric dimethylarginine (SDMA)
Why is SDMA a good marker of GFR?
> 90% eliminated by the kidneys
Freely filtered across the glomerulus without tubular reabsorption
How much kidney function must be lost for SDMA to be elevated?
30-40% decline in function (earlier marker than creatinine)
In dogs and cats with CKD, how much sooner does SDMA increase compared to creatinine
Cats: SDMA increased 17 months before creatinine
Dogs: 10 months
How long must kidney function be decreased to call it chronic kidney disease? Why?
> 3 months
It can take up to 3 months for renal compensatory hypertrophy to occur after an AKI
Staging CKD should be based on what?
A minimum of 2 stable creatinine values obtained when the patient is fasted and well hydrated, obtained at least a few weeks apart
When should pets with borderline proteinuria be re-evaluated?
In 2 months
Name 5 benefits of a renal diet
- Low sodium and phosphorus
- Added B vitamins
- Increased caloric density
- Soluble fiber
- Neutral effect on acid/base balance
- Omega-3 fatty acids/antioxidants
Limiting dietary phosphorus is indicated for what IRIS stages of CKD?
II through IV
Limiting dietary protein is indicated in what IRIS stages of CKD?
III and IV in dogs
II through IV in cats
In dogs with CKD fed a renal diet vs a maintenance diet, what was the symptom free interval? Risk of death and MST?
- Symptom free interval 600 days vs 250 days
- Risk of death from renal causes reduced by 69%
- MST 600 days vs 190 days
In cats with CKD fed a renal diet vs a maintenance diet, what was the MST?
MST 630 days vs 264 days
When should phosphorus be rechecked after starting a renal diet?
4-6 weeks, if no improvement, add binding agent
What are the clinical signs of aluminum toxicosis in patients on aluminum containing phosphate binders?
Cranial, peripheral, junctional neuropathies - ataxia, weakness, absence of patellar reflexes, decreased withdrawal, tetraparesis
When should bicarbonate supplementation be considered?
Plasma bicarbonate <15 mmol/L
What are two oral options for alkalization therapy?
Potassium citrate and sodium bicarbonate
What antihypertensive agent may promote hypokalemia in CKD cats?
Amlodipine
What are the clinical signs of hypokalemic myopathy?
Muscle weakness, cervical ventroflexion
Which erythrocyte stimulating agent is more likely to induce anti-EPO antibodies? How often does it occur?
Epoetin alfa
25% of cats and up to 50% of dogs
What can anti-EPO antibodies cause?
Markedly suppress erythropoiesis and lead to pure red cell aplasia
Why might hypertension develop while on erythrocyte stimulating agents?
Chronic hypoxia leads to vasodilation, giving darbepoietin and increasing oxygen delivery may lead to reversal of this vasodilation, this increasing vascular resistance and BP
When are erythrocyte stimulating agents indicated?
Advanced CKD (stages III and IV) with a PCV <22% and clinical signs attributed to anemia
What weekly increase in PCV is expected with darbepoietin?
1-3% increase per week - more rapid changes are more likely to cause hypertension
Name 4 mechanisms of action of calcitriol
- Enhances GI uptake of Ca and PO4
- Inhibits PTH synthesis and secretion
- Suppresses parathyroid growth
- Activates cellular receptors
How does hyperphosphatemia suppress calcitriol production?
Inhibits renal 1-alpha-hydroxylase activity, thus limiting the conversion of calcidiol to calcitriol
What is the SDMA and creatinine for dogs and cats with Stage I CKD?
Dogs: creatinine <1.4, SDMA <18
Cats: creatinine <1.6, SDMA <18
What is the SDMA and creatinine for dogs and cats with Stage II CKD?
Dogs:
- Creatinine 1.4-2.8
- SDMA 18-35
Cats:
- Creatinine 1.6-2.8
- SDMA 18-25
What is the SDMA and creatinine for dogs and cats with Stage III CKD?
Dogs:
- Creatinine 2.9-5.0
- SDMA 36-54
Cats:
- Creatinine 2.9-5.0
- SDMA 26-38
What is the SDMA and creatinine for dogs and cats with Stage IV CKD?
Dogs:
- Creatinine >5
- SDMA >54
Cats:
- Creatinine >5
- SDMA >38
What blood pressure is considered pre-hypertensive? Hypertensive? Severely hypertensive?
Pre-hypertensive: 140-159
Hypertensive: 160-179
Severely hypertensive: >180
What should the serum phosphorus be for stage I and II CKD patients? Stage III? Stage IV?
Stage I and II: <4.6 mg/dL
Stage III: <5.0 mg/dL
Stage IV: <6.0 mg/dL
Should never drop below 2.7
Cats with a serum phosphorus within the IRIS target (<4.5 mg/dL) are at increased risk of what after introducing a renal diet?
Hypercalcemia
What test should be performed in cats with a serum phosphorus <4.5 before introducing a renal diet? How should you interpret/act on the results?
FGF23
- If the FGF23 >400 pg/nL in the absence of hypercalcemia, anemia, or marked inflammatory disease, start phosphorus restriction. Monitor serum calcium - if tCa >12, switch to a less phosphorus restricted diet
If serum phosphorus levels normalize with a renal diet +/- binders, FGF23 should be measured to see if further phosphorus restriction is beneficial. How should the results be interpreted?
If FGF23 >700 pg/nL, further phosphate restriction is indicated.
If FGF23 is <500 pg/nL, things are well controlled
What factors other than hyperphosphatemia can increase FGF23?
Hypercalcemia, anemia, marked inflammatory disease
What markers of fibrosis were increased in cats with CKD compared to non-azotemic cats and were positively associated with creatinine?
MMP2, MMP7 and TIMP1
How does functional iron deficiency occur?
- Inflammation leads to the expression of hepcidin, an acute phase protein.
- Hepcidin down regulates expression of ferroportin, which is a membrane iron transport protein.
- This leads to decreased intestinal iron absorption and sequestration of iron in reticuloendothelial cells, thus limiting the iron available in the body
What acute phase proteins are increased in CKD cats compared to healthy controls?
SAA and hepcidin - positive correlation with creatinine
Describe the iron status of CKD cats compared to healthy controls
Decreased total iron and total iron-binding capacity - suggestive of a functional iron deficiency
Decreased TIBC is worse in anemic CKD cats
How did the gastric pH and serum gastrin concentrations of CKD cats compare to healthy controls?
No difference - no evidence of hyperacidity in CKD cats, no evidence for acid suppression
Cats with CKD lost what percent of their body weight in the 12 months after diagnosis? How did this correlate with survival?
8.9%
Cats <4.2 kg at the time of diagnosis had shorter survival times
What risk factors for the development of CKD have been identified in cats?
Annual/frequent vaccination, moderate to severe dental disease (PD stage 3 or 4)
Once daily omeprazole increased food consumption by what percent in CKD cats?
2.7% - statistically significant, but negligible
Don’t use unless GI ulceration is present
Administration of transdermal mirtazepine resulted in what changes in CKD cats?
Increase in weight, appetite, and rate of food consumption
- No difference in 3.75mg vs 1.88 mg
What drug is most effective at controlling proteinuria in cats with CKD?
Telmisartan - decreased proteinuria at all time points
Benazepril did not
When administered to CKD cats, beraprost sodium (a prostacyclin analogue) caused what changes compared to a control group?
The control group displayed progression in azotemia (creat 2.8 to 3.2) over 180 days, where the treatment group did not (2.4 to 2.5)
Phosphorus/calcium ratio increase in the placebo group but not the treatment group
What effects did maropitant have on CKD cats compared to placebo?
Decreased vomiting, but no change in appetite scores, activity scores, or weight
The use of low dose meloxicam in CKD cats resulted in the clinicopathologic changes?
No change in creatinine/BUN/SDMA/GFR but caused increased proteinuria (UPC 0.33 vs 0.1)
Magnesium concentrations are inversely associated with what hormone in CKD cats? How did it affect survival?
FGF23
Hypomagnesemia was associated with increased risk of death
In dogs treated with darbepoietin, what percent achieved a PCV of >30% and what percent achieved an increase in PCV of 10%? How long did it take
PCV >30%: 85% of dogs
PCV increase of 10%: 67% of dogs
Took 29 days
In dogs treated with darbepoietin, how long could the dosing period be extended before PCV dropped again?
21 days maximum
In dogs treated with darbepoietin, what were the observed side effects?
Hypertension (36%), seizures (15%), PRCA (6%)
What factors were negatively associated with survival in dogs with CKD?
BCS <4, muscle atrophy, increased creatinine, hyperphosphatemia, increased FGF23, increased UPC
A direct correlation has been found between what marker of cardiac disease and CKD in dogs?
Direct correlation between ACVIM MMVD class and IRIS stage - dogs with CHF had a higher prevalence of CKD (25%) than dogs without CHF (15%)
What is the definition of renal dysplasia (now renamed juvenile onset CKD due to renal maldevelopment)
Abnormal, disorganized differentiation of the renal parenchyma
What are histopathologic features of renal dysplasia?
- Evidence of inappropriate differentiation - immature/fetal nephrons, persistent metanephric ducts
- Hypertrophy of the normal, functioning nephrons
- Atypical tubular epithelial proliferation
- Dysontogenic metaplasia
- Secondary interstitial nephritis, fibrosis, etc
In what breeds has renal dysplasia been well characterized/proven?
Lhasa apso, Shih Tzu
Persians
What is the prognosis for renal dysplasia?
Severe: >25% of glomeruli affected
- End stage at 3-6 months
Moderate: 10-25% of glomeruli affected
- Progressive CKD at 1-3 years
Mild: <10% of glomeruli affected
- CKD as an adult, may have normal lifespan
What causes Alport Syndrome?
Heredity nephritis - results from a genetic defect of basement membrane type IV collage
Loss of appropriate cell anchoring to the GBM => glomerulosclerosis => renal failure
Alport syndrome is autosomal recessive in what dog breeds?
English Cocker Spaniels
American Eskimo
Alport syndrome is autosomal dominant in what dog breeds?
Bull Terriers
Dalmatians
Beagle
Alport syndrome is X-linked dominant in what dog breeds?
Samoyeds
What are the clinical signs of dogs with Alport syndrome?
Signs are worse in X-linked and autosomal recessive
- Marked proteinuria at <6 months of age (UPC up to 10 to 20)
- Hematuria
- Edema, ascites, hypertension are uncommon
What is the prognosis for Alport syndrome?
Depends on breed
- Samoyeds: males die by 1 year of age, females progress slowly
- English Cockers: severe CKD by 1-2 years
- Bull Terriers and Dalmatians: CKD can appear by 7 months or not until 7-8 years
What is the cause of collagenofibrotic glomerulopathy or type III glomerulopathy?
Expansion of the mesangium and capillary wall by accumulations of collagen fibrils and fibronectin - also a form of glomerulosclerosis
What is the clinical presentation of dogs with collagenofibrotic glomerulopathy?
Young dogs of either sex with SEVERE proteinuria and eventually azotemia
Ultimately fatal :(
What dog breeds are affected by polycystic kidney disease? How does the presentation of the disease vary with breed?
Bull Terrier: cysts are limited to the kidneys, azotemia develops in the first years of life
Cairn Terrier and West Highland white terrier: cysts in both the kidneys and liver, azotemia within the first months of life
What cat breed is most commonly affected by polycystic kidney disease? What is the gene mutation involved?
Persians - 40% of them
- Autosomal dominant, single nucleotide mutation in PKD1 (premature stop codon)
- Homozygous is embryonic lethal
Where do Persian cats develop cysts in polycystic kidney disease?
Kidneys, liver, and pancreas
What causes CKD in patients with polycystic kidney disease?
Cysts grow slowly over time, resulting in a decrease in the amount of normal renal parenchyma, progressive tubulointerstitial nephritis and fibrosis
In both dogs and cats, renal cysts will be visible on ultrasound by what age?
6 months (if not there by 6 months, no PKD)
What is the average age of CKD onset of CKD in Persians with polycystic kidney disease?
6 years
Where is amyloid deposited in Shar-Pei dogs? How do they present?
- Renal medulla is primarily affected
- 1/2 of dogs have glomerular involvement
- Present with more severe azotemia, milder proteinuria
Where is amyloid deposited in non-Shar Pei dogs? How do they present?
- Renal cortex and glomeruli primarily affected
- Present with moderate to marked proteinuria (UPC >2) with or without azotemia (present in later stages)
What breed develops Fanconi Syndrome and what is the inheritance pattern?
Basenjis (10%) - autosomal recessive
What is Fanconi syndrome?
Defect of the proximal tubule, leading to malabsorption
What is the presentation the clinicopathologic abnormalities present with Fanconi syndrome?
- Abnormal glucose absorption => glucosuria, osmotic diuresis => PU/PD, UTIs
- Abnormal amino acid absorption => hypoaminoacidemia, proteinuria => poor body condition
- Abnormal fractional excretion of solutes => acidosis, hypokalemia, hypophosphatemia => panting, weakness
What is the typical age of onset for Fanconi syndrome in Basenjis and when should you start monitoring?
5-7 years
Start monitoring via monthly urine dipstick at 3 years of age
