CKD Flashcards
Why does phosphorus increase in CKD
GFR is the primary determinant of P entering the renal tubules. As GFR decreases in the face of CKD, the amount of filtrate decreases.
As CKD worsens and sPi increases the amount of Pi entering each nephron increases despite a reduction in GFR
In CKD, the load of phosphorus per single nephron is elevated because of the reduction in the number of functional nephrons.
Role of FGF23 in Pi changes in CKD as it progresses
In CKD FGF23 is increased due to increased sPi (from reduced GFR) and PTH
–> increased excretion of Pi (inhibits reabsorption) and inhibition of Vit D formation (which blocks intestinal Pi absorption)
–> maintain normal sPi
As kidney disease progresses there is reduced alpha klotho production –> FGF23 cannot exert its effects
–> increased reabsorption of Pi –> increased sPi and PTH reaching a new equilibrium state.
Why is FGF 23 a potential marker for mineral bone disturbance in CKD
It is the adaptive response to whole body Pi retention caused by reduced GFR.
It is also removed predominantly by renal excretion
FGF23 levels appear to be an independent risk factor for all cause mortality at initial diagnosis of CKD indicating that at some point the increase in FGF in response to sPi increase becomes maladaptive (the point at which this occurs is not yet determined but likely is affected by alpha klotho production)
Causes other than sPi that increase FGF 23
Inflammatory cytokines: TNFa, IL1B, IL 6
Iron deficiency
Possible mechanism that FGF23 may harm renal tubules
Inhibits proximal tubule reabsorption of Pi –> increased tubular fluid Pi
Pi can form calciprotein particles that bind TLR4 in the tubular lumen –> internalised and causes cellular stress
Whether or not FGF23 has a direct detrimental effect on the kidney once plasma concentrations start to increase in CKD patients remains to be determined
Systemic effects of maladaptive increase in FGF 23
evidence (from in vitro studies and laboratory animal studies) that FGF23 contributes to cardiac hypertrophy associated with CKD and vascular calcification. Both of these effects contribute to the cardiovascular disease which is often the cause of death in CKD human patients
Similar evidence is not available in veterinary literature
Evidence of direct effects of FGF23 in veterinary medicine
In one long-term longitudinal study of cats with CKD, 19% died or were euthanised because of a cardiovascular complication of their CKD
FGF23 concentration tends to be higher and plasma magnesium concentration tends to be lower in cats with hypertension and CKD when compared to normotensive CKD feline patients
appears to be a strong correlation between plasma FGF23 concentration and plasma aldosterone concentration in the cat suggesting a role for FGF23 in the pathophysiology of hypertension associated with feline CKD
What is the trade-off hypothesis in CKD
Renal adaptive and compensatory processes (ie RAAS and alterations to blood flow) maximise the residual function of remaining nephrons to sustain homeostasis but the trade off is there is ongoing damage and loss of these remaining nephrons.
Prerenal and postrenal azotaemia to exist with CKD and these may be reversible which will reduce the degree of azotaemia
Once corrected though, further improvement of renal function should not be expected because the compensatory/adaptive mechanisms to improve renal function have largely already occurred → promotion of progressive loss of remaining nephrons and renal function.
Cat and dog breeds with increased CKD risk
Maine coon, Abyssinian, Siamese, Russian blue and burmese
Cocker spaniels and CKCS had increased odds of CKD.
Potential causes of CKD in dogs and cats
familial, congenital or acquired conditions
In dogs associated with borreliosis (lyme nephritis) and leishmaniasis in some geographic locations.
In cats, Several infectious agents have been suggested as possible factors, as have vaccinations → no causative link has been established.
Recent studies have concluded feline CKD is associated with shortened telomeres and increased cellular senescence in affected kidneys.
Potentially reversible causes of renal dysfunction
pyelonephritis, obstructive uropathy, nephrolithiasis, renal lymphoma, hyperCa nephropathy, perinephric pseudocyst, and some glomerulopathies
Prerenal, postrenal and active renal disease complications should be treated first before IRIS CKD staging is performed
Prognostic factors for dogs and cats with CKD
In general cats with CKD survive longer than dogs.
CATS: Stage and serum PO4 were the only baseline parameters that significantly affected survival time
Hypertension did not appear to be a primary determinant of prognosis but if treated it improves proteinuria which in turn is assocaited with improved MST.
DOGS: IRIS stage, and BUN concentration.
Proteinuria has been identified as a risk factor for development of clinical signs of uraemia and death
Hypertension in dogs is associated with prognosis (unlike in cats) Dogs with the highest baseline systolic BP have a greater decline in renal function over time and have increased risk of uraemic crises
Rate of progression of congenital disease is slower than for dogs that develop acquired CKD (also true in young dogs that develop acquired CKD)
IRIS Stage Guidelines
I - non-azotemic
Dogs sCr <125; SDMA <18
Cats: sCr <140, SDMA <18
- inadequate urine concentrating ability,
- abnormal appearance of kidneys on imaging.
- persistent proteinuria
II - Dogs sCr 125-250 SDMA 18-35
Cats: sCr 140-250, SDMA 18-25
Usually mild or absent clinical signs (PUPD)
III - Dogs sCr 250-440 SDMA 36 - 54
Cats: sCr 250-440, SDMA 26 - 38
More likely to have clinical signs referrable to kidney function loss.
Typically progressive
IV - Dogs sCr >440 SDMA >57
Cats: sCr >440, SDMA >38
Clinical signs of uraemia. Aim to ameliorate these symptoms.
IRIS guidelines suggest SDMA levels be used to modify staging in patients with marked muscle mass reduction. So if SDMA stage is higher and patient has low body muscle mass then adjust to higher stage
IRIS Substages
HYPERTENSION
< 140 normotensive, minimal TOD risk
140-160 pre-hypertensive, mild risk of TOD
160-179 hypertensive, moderate risk of TOD
> 180, severe, high risk of TOD
PROTEINURIA
Recommended UPCR is checked 2-3 times over 2 weeks and the average used.
<0.2 - normal
0.2-0.5 - borderline (need monitoring)
>0.5 (0.4 for cats) - proteinuric
Mechanism of RSHPTH
Reduced excretion of Pi due to decrease in GFR from nephron loss
→ PTH stimulated production of calcitriol and FGF23 to increase Pi excretion → compensates in early disease
→ ongoing nephron loss → calcitriol deficiency
→ reduced Ca absorption and lack of negative feedback to PT gland → more PTH made
↓ calcitriol → skeletal resistance to the effects of PTH (less Ca released), and elevates the set point for Ca-induced suppression of PTH secretion
–> normal iCa but elevated PTH
Management of Stage I CKD in dog and cat
Remove causes of renal damage: nephrotoxic medications, pre/post-renal abnormalities; rule out treatable disease such as nephroliths or pyelonephritis
assess for proteinuria, hypertension and treat.
If evidence of protein loss then also add anti-platelet medication (clopidogrel)
Assess sPi and if normal also measure FGF23 - phosphorus restriction indicated if either is elevated
Treatment for Stage II CKD
Implementation of renal diet may slow progression of disease and may be easier to transition when appetite is unaffected
Continue assessment of Pi and FGF23
Assessfor hypoK in cats as well
Treatment for stage III CKD in dogs/cat
Renal diet strongly recommended
Add phos binders if still over recommended levels
Treat anaemia if PCV <20%
Give HCO3 orally if persistent acidosis after diet implementation (HCO3 <18 for dogs <16 for cats)
Drugs that rely predominantly on renal function for their clearance from the body should be used with caution
Management of GI upset. In cats mirtazepine reduces vomiting and improves appetite.
Management of Stage IV CKD
Avoid protein/caloric malnutrition - O-tube placement may be considered
Prevent dehydration with parenteral or supplemental water (O-tube good for this too)
Dialysis or renal transplant if cannot be managed medically
Key Diet factors in CKD MAnagement
Goals: 1) ameliorate or prevent clinical consequences of CKD including signs of uremia; 2) slow progression of CKD and prolong survival; 3) minimise derangements of electrolyte, calcium and phosphorus, and acid-base balance; and 4) maintain adequate nutrition
Omega 3 PUFA and antioxidants - lowers mortality and improves renal function (increasing anti-inflammatory PG production and reducing oxidative stress)
Phosphorus restriction - prevent RSHPTH and CKD-MBD. author typically considers phosphorus as the primary nutrient of concern for CKD, and subsequently aims to provide less than 1.5 g phosphorus/Mcal (150 mg/100 kcal) to dogs and cats with CKD
High caloric density to minimise amount required as appetite dysregulation is common
Protein restriction - decrease dietary protein enough to decrease proteinuria, but not so much as to contribute to LBM loss. In proteinuric renal disease there is No concrete evidence that ↓ dietary protein slows progression, but it does ↓ urinary protein excretion and ↑ serum albumin
Electrolyte
Recommended monitoring in CKD based on stage
Initial evaluation may require visits every 2-4 weeks until the initial response to therapy is established
Stage I CKD - may require checks only every 6-12 months, more frequently if there is substantial proteinuria.
Stage II - in general monitoring every 3-6 months in cats and every 2-4 months in dogs.
Stage III - monitor every 2-4 months depending on stability of disease/renal function.
REcommendations from JSAP NSAIDS in feline CKD
Both COX-1 and COX-2 are constitutively expressed in the kidneys, and their metabolites are important mediators for the maintenance of renal perfusion and auto-regulation
Prostaglandins such as PGE2 and PGI2 promote vasodilation and inhibition of Na+ reabsorption, while thromboxane A2 modulates renin production and vasoconstriction
Despite concerns, long-term NSAID therapy was found to be safe and efficacious when administered to cats with OA (mean age: 12.9 years old) for approximately 6 months(Gunew et al. 2008). In this prospective study, no difference in serum creatinine levels were found between cats treated with meloxicam or placebo
current literature on long-term use of NSAIDs in cats with CKD has some limitations. The two studies of meloxicam in cats with CKD and OA were retrospective, and this type of study design has intrinsic limitations and is subject to numerous biases. Importantly, the author of those retrospective studies decided which cats to medicate with meloxicam, only medicating cats that were more healthy looking and in better body condition
In humans, there is similar controversy. In a systematic review including nearly 12,500 individuals receiving NSAIDs and 23,900 controls, eight of nine studies failed to identify an increased risk of chronic renal impairment associated with NSAID consumption
NSAID-associated renal toxicity of clinical significance is generally dose-related and occurs in less than 1% of the population
WSAVA GPC recommended considerations for administration of NSAIDs to cats with CKD
Stable CKD
Safety on NSAID in cats with advanced
Stage III/VI CKD are less studied
Long-term maintenance of hydration adn free access to water
Use of minimal effective dose based on owner observations.
Ongoing monitoring should be performed via routine health checks, including changes in bodyweight, body condition scores and blood pressure, and clinical pathology tests such as haematology, serum biochemistry profile and urinalysis
Different phosphate binder options
Aluminium hydroxide - give with food
LAnthanum carbonate - divide dose b/w meals
Sevelamer - may affect vitamin absorption or cause GI upset
Ca-CO3 - may cause hypercalcemia
Epakitin (chitosan)
Evidence/recommendations for vitamin D supplementation in CKD
↓ calcitriol → skeletal resistance to the effects of PTH (less Ca released), and elevates the set point for Ca-induced suppression of PTH secretion
Cats and Dogs with both CKD and nonazotemic PLN tend to have lower serum calcidiol and calcitriol
Enhances GI Ca and PO4 uptake, inhibits PTH synthesis/secretion, suppresses parathyroid gland growth and activates cellular receptors. While clinical benefits of these individual actions have not been demonstrated the use of calcitriol therapy in CKD patients has been shown to reduce mortality in stage III and IV CKD in dogs
NB: There does not seem to be a clear relationship between dietary vitamin D3 (ie, cholecalciferol) intake and subsequent serum 25(OH)D concentrations in dogs
Use in cats is only speculative (and not currently recommended).
Prospective survival analysis studies lacking - likely to be more complicated than ALLL needing to be supplemented.
Major sequelae of CKD
Anaemia
Gastritis and anorexia
RSHPTH
HyperPi
Polyuria
Hypertension
Proteinuria
Acidosis
Hypokalaemia
+/- Hypercalcemia
Pathogenesis of polyuria in CKD
↑ solute load/surviving nephron;
Impaired genesis of hypertonic medullary gradient (due to destruction of renal architecture)
Impairment in renal responsiveness to ADH.
Pathogenesis of hypertension in CKD
RAAS → Na and fluid retention
Reduced ECV due ongoing polyuria → SNS activity and further RAAS activation and arterial vasoconstriction via alpha adrenergic receptors.
in CKD there is a dysregulation of RAAS which favours the development or exacerbation of systemic hypertension. The exact nature of these disturbances is multifactorial, complex and not fully understood - much extrapolated from human med which may not be analogous
Recommended Tx in hypertension for cats with CKD - new publications
CATS: Ca channel blockers (amlodipine) are first choice because of established efficacy in cats with CKD or idiopathic hypertension. (ACVIM SHT consensus)
Despite dramatic antihypertensive efficacy, longitudinal control of SBP with amlodipine besylate has not been shown to increase survival time in hypertensive cats. Use may activate intrarenal RAAS
ARB: comparison of telmisartan to benazepril in proteinuric azotaemic cats - At Day 180, UP/C compared to baseline in the telmisartan group was significantly lower than baseline but had not changed significantly in benazepril group
Telmisartan has proven efficacy with mild to moderate hypertension and proteinuria. Use in severe hypertension has not been evaluated and consensus still recommends CCB as first choice option due to proven efficacy
ACEi - not recommended as first line as only cause small decrease in SBP
Recommended Tx in hypertension for dogs with CKD - new publications
ACVIM SHT Consensus
DOGS: ACEi as first line, often need CCB as second line in severe disease.
In dogs with concurrent CKD, a clinically relevant decrease in proteinuria (UPCR decreased by ≥50%, preferably to <0.5) is a secondary goal of antihypertensive treatment
JVIM 2021- ACEi, ARB or both effect on proteinuria and SHT
-> ACEi + ARB caused significantly lower UPCR in comparison to either sole treatment
Possible aetiologies of CKD in cats
Aetiology – chronic tubulointerstitial nephritis & renal fibrosis
toxic insults
hypoxia
chronic glomerulonephritis
upper urinary tract infections
viral infections (Morbillivirus)
Amyloidosis
PKD
renal lymphoma
hypercalcaemic nephropathy
congenital disorders
