Renal Flashcards
Function of the proximal tubule?
Isosmotic reabsorption of 70 % filtered water and NaCl, 90 % bicarb, NH3 production, reabsorption of almost all glucose and amino acids, reabsorption of potassium, phosphate, calcium, magnesium, urea and urate, secretion of organic anions and cations
Function of loop of henle?
Countercurrent multiplier, reabsorption 15-25 % filtered NaCl, active regulation of magnesium excretion
Function of distal tubule?
Small amount of NaCl absorption, active regulation of calcium excretion
Function of connecting segment/cortical collecting duct?
Aldosterone-mediated potassium secretion by principal cells, H+ secretion and potassium reabsorption by alpha intercalated cells, ADH mediated water reabsorption
Function of medullary collecting duct?
Potassium reabsorption or secretion, final NaCl reabsorption, ADH mediated water and urea reabsorption, H+ and NH3 secretion
Why is there more filtration in the glomerular capillaries than systemic?
More surface area, but not constant and can change eg with mesangial cell contraction under ATII influence
What substances constrict/relax the glomerular vessels?
Constrict afferent and efferent - norepinephrine, ATII, endothelin, thromboxane
Constrict just efferent - vasopressin
Relax both - acetylcholine, NO, dopamine, bradykinin, prostacyclin, PGI2
Relax afferent - PGE2
NE, ATII and ADH promote production of prostaglandins
What is tubuloglomerular feedback?
Local intrarenal negative feedback mechanism for individual nephrons:
Increased NaCl in the distal tubule sensed by extraglomerular mesangial cells of the juxtaglomerular apparatus, sensed by tubular cells of macular densa (transport of NaCl across them - requires Na K 2Cl transporter and ROMK potassium channel luminal, and NaKATPase basolateral)
Transcellular NaCl transport + ATII causes afferent constriction and decrease GFR to minimise NaCl loss
What transporter does furosemide inhibit?
NaK2Cl in loop of Henle, compete with Cl
What transporter do thiazides inhibit?
NaCl in distal convoluted tubule
What is sodium absorbed with in the PCT?
Glucose, amino acids, phosphate, bicarbonate
What is sodium absorbed with in the DCT/LoH?
Chloride
What transporters mediate luminal uptake of glucose in the PCT?
SGLT2 - high capacity low affinity, first and second portion
SGLT1 - low capacity high affinity, third portion
Saturatable
What mediates PCT phosphate absorption?
NaPi-IIa and IIc transporters
Low Tmax so ready excretion of phosphate at high conc cf glucose
PTH decreases Tmax and causes excretion
How is urea reabsorbed?
Passive (decreased with high tubular flow rates)
Facilitated transporters - UTA1/A3 in inner medulla collecting duct, ADH dependent, urea concentrates in interstitium
Can reenter thin descending LoH via UTA2, and reabsorbed to enter vasa recta (venous) and then arterial (have UTB) - countercurrent exchange
Impermeable to urea - DCT, cortical collecting duct, outer medullary collecting duct
What are the urinary concentrating mechanisms?
NaCl transport without water in ascending LoH causes hyper osmotic medullary interstitium
ADH increases water permeability of the collecting duct, tubular fluid equilibrates with hyper osmotic interstitium
What controls inner medullary collecting duct urea absorption?
ADH
What effect does aldosterone have in cortical collecting duct?
Sodium and chloride absorption and therefore water absorption
How is urine concentrated without ADH?
GFR decreased by dehydration, PCT reabsorbs more sodium and water
What is the vasa recta for?
Gains solute as moves distally, gains water as moves proximally. Interstitial osmolality increases as move distally (ascending LoH solute absorption) and decreases as move proximally
Where is renin from and what stimulates its release?
Juxtaglomerular apparatus, vascular endothelium, adrenal gland, brain.
Decreased renal perfusion sensed by afferent arterioles of granular cells of JGA, hypotension stimulation cardiac/arterial baroreceptors with SNS activity and catecholamines (beta 1 adrenergic receptors), decreased distal tubular flow or NaCl depletion (macula densa)
Inhibited by ATII
What are the effects of ATII?
Arteriolar vasoconstriction (most sensitive renal splanchnic cutaneous)
Facilitates NE release from adrenal medulla and sympathetic nerves
Increases PCT sodium absorption d/t NaH antiporter luminal membrane
Increases aldosterone secretion
TXA2 mediated glomerular vasoconstriction (efferent > afferent)
Increased sodium and water reabsorption
Mesangial contraction, decrease surface area
Release of vasodilatory PGE2 and I2
What inhibits 1alphahydroxylase?
Calcium, vitamin D, decreased PTH, increased phosphate
Definition of CKD?
> 2-3 m permanent irreversible loss of functioning nephrons
What does carbamylated haemoglobin measure?
Chronic measure of increases in circulating urea
Ideal GFR marker
Sole renal filtration, no metabolism, no protein binding, no tubular secretion, non toxic, don’t affect GFR
NB male dog active creatinine tubular secretion
Urinary clearance?
Urine flow rate x conc solute in urine
conc solute in plasma
What cats have increased creatinine?
Birman
What is SDMA?
Dimethylated derivative of arginine, produced from intranuclear L-arginine residues by protein arginine methyltransferase
What is cystitin C?
LMW protein, proteinase inhibitor, intracellular housekeeping gene production
Not protein bound and freely filtered, resorbed by megalin endocytosis in proximal tubules and catabolised
No secretion
Might be increased in tubular dysfunction?
What does the sulfosalicylic acid test check for?
Globulin/bence jones protein
Why would you measure microalbuminuria?
If suspect hereditary glomerular disease - more sensitive cf UPCR or dipstick
Needs to be persistent > 2 w to be of value
What impacts UPCR?
Active sediment, marked haematuria, hospitalisation, daily variability
Cysto does not change
If > 4 pool samples
Has to change 35 % if > 12 or 80 % if < 0.5 to be clin relevant change
When should a renal biopsy be pursued?
UPCR persistently > 3.5, no response anti proteinurics, progressive proteinuria or azotaemia despite adequate management, if considering immunosuppressive management
Important things to do before renal biopsy?
Control BP, discontinue anticoagulants, check haemostasis
Contraindications for renal biopsy?
Stage 4 renal disease, tubulointerstitial rather than glomerular, hydronephrosis, pyelonephritis, haemostic disorder, suspect amyloidosis, suspect hereditary, renal abscess
What media do renal biopsies go into?
Formalin (standard)
Michel’s medium (IF)
Glutaraldehyde (TEM)
How to calculate fractional excretion of electrolytes?
urine conc x (plasma/urine creat) x plasma conc
x 100
Increases as GFR decreases - electrolytes used as hypertrophy/compensatory
What casts are not necessarily abnormal?
Rare hyaline/granular
What are hyaline casts?
Mucoprotein, TammHorsfall protein, uromodulin, albumin
Colourless/cylindrical
Increase with marked proteinuria and dissolve in urine
Epithelial casts?
Direct tubular damage eg gentamicin
Granular casts?
Ischaemic/nephrotoxic insult - partially degraded cellular casts
Waxy casts?
Due to tubular stasis
What causes renal hyperechogenicity?
Non specific - glomerulonephritis, acute tubular necrosis, lepto, FIP end stage CKD
Dramatic in ethylene glycol tox
Renal dysplasia - corr with histopath
Hypoechoic subcapsular thickening?
Lymphoma
Medullary rim sign?
Ethylene glycol
NB outer medulla may be hyper normally
Medullary band sign?
Inner medulla hyper echoic - lepto
AKI classification?
1: Non azotaemic AKI - increase creatinine by 27 over 48h, clinical findings eg documented history or volume response, oliguria < 1
2: Mild, 150 - 221
3: Moderate/severe 230 - 442
4: 451 - 884
5: > 884
Mortality association with azotaemia?
Increased mortality in ICU even if increased creatinine without azotaemia
Hypothermia px indicator
Causes of AKI?
Hypoperfusion (haemodynamic), intrinsic, post
What factors make the kidney susceptible to injury?
High cardiac output, high metabolic demand, toxicity potential
What determines renal blood flow?
Perfusion pressure, cardiac output, intravascular volume
What defines volume response in AKI?
If increase UOP to > 1ml/kg/hr with fluid challenge or decrease creatinine to baseline over 48h
What happens if you don’t address haemodynamic/volume responsive AKI?
Progresss to intrinsic
What is required to progress from haemodynamic to intrinsic AKI?
Other factors eg local or systemic inflamm, infrarenal blood flow distribution change, microcirculatory dysfunction/glomerular haemodynamics
Phases of AKI?
Initiation - injury
Extension - cellular damage - hypoxia/inflamm
Maintenance - static 1-3 w
Recovery - increased UOP increased Na in urine due to decreased sodium transporters, Na loss can cause vol depletion
What is fenoldopam?
Dopamine 1 receptor agonist - causes renal vasodilation, inhibits ADH AT II and NaKATPase
Increases UOP
What are the cellular mechanisms underlying AKI?
Hypoperfusion, tubular dysfunction, ischaemic injury
Explain intrarenal vasoconstriction AKI
Vasoconstriction (decrease NO injured cells increased ET) - decrease GFR, cause ischaemic damage to cells
Decreased O2
Decreased cell energy metab
Mitochondrial dysfunction (calcium)
Explain ischaemic damage AKI
Reperfusion/oxidant injury, intracellular acidosis, phospholipase/protease activation
Explain tubule dysfunction AKI
Cell swelling
Loss of fence, transporters on wrong side
Tubular obstruction detached cells
Leaking junctions back leak fluid
Energy depletion disrupts cell cytoskeleton
What potentiates contrast mediated injury?
Hyponatraemia
Ionic contrast
Decreased BP and vasoconstriction renal circulation
What part of the glomerulus does vasopressin constrict most?
Efferent - maintains GFR
Why are aminoglycosides nephrotoxic?
Not metabolised, low molecular weight and water soluble. Ionised to cationic complexes and bind anionic sites on PCT cells, internalised and concentrate there.
Potentiation/risk factors = multiple daily dosing, increased concentration, electrolytes low, acidosis, furosemide,antiprostaglandin, dehydration
30S ribosomal binding
Why are tetracyclines nephrotoxic?
If expired - metabolites in mitochondria, interfere with PCT oxidative enzymes
Penicillin and sulphonamide nephrotox?
Hapten/hypersensitivity/crystallisation
Role of prostaglandins in the glomerulus?
Prostaglandin maintains afferent arteriole dilation to maintain GFR when systemic vasoconstriction is present
Neutrophil gelatinase associated lipocalin?
Same things found cats & dogs
NGAL - increased before creatinine in AKI and CKD
Corr with AKI grade
Poss higher in intrinsic vs volume AKI and inflammatory AKI
No diff outcome AKI
Predict progression CKD
Made in neuts, increased production, decreased absorption and increased secretion during tubular injury
What is insensible loss?
22 ml/kg/day
What to give to an anuric patient fluid-wise?
Only insensible loss (may need to not give this if over hydrated)
What effect would increased chloride in the DCT have?
Afferent glomerular vasoconstriction (higher chloride increase incidence AKI?)
What factors to check to ascertain whether an animal is oligoanuric?
Optimise renal perfusion, BP MAP > 60, systolic > 80 and check cath
NB relative versus absolute oliguria
Mannitol mechanism of action?
Osmotic diuretic, extracellular volume expansion
Inhibits renin and renal sodium reabsorption
Increases tubular flow, decreases vascular resistance, decreases cell swelling, protects cf vascular congestion/RBC aggregation, scavenges free radicals, increases intrarenal prostaglandin and vasodilation
Increases renal blow flow and GFR - increases solute excretion, ANP, decreases the mitochondrial response to the calcium influx and therefore decreases progression from sublethal to lethal cell injury
BUT no evidence that it improves AKI
Can’t use if dehydrated or over hydrated
Furosemide mechanism of action?
Loop diuretic - inhibits NaK2Cl pump in LoH - increases tubular flow with no increase in GFR
Makes basal NaK pump unnecessary
Decreases medullary O2 consumption
Renal vasodilatory effects
Use for over hydration/hyperkalaemia?
CRI gives more sustained diuresis with lower dose
Calcium channel antagonists?
Eg diltiazam, which might help with more complete resolution in dogs with lepto
Reverse vasoconstriction, dilate mostly afferent, inhibit glomerular feedback-mediated vasoconstriction
GFR independent natriuresis
Peritoneal dialysis?
Probably more helpful in cats
Mechanisms of calcium, magnesium and phosphate changes in AKI?
Increased calcium - usually inc total with N ionised but can be increased if decreased GFR and no excretion
Decreased calcium - complex with phosphate
Phosphate - decreased excretion
Magnesium - decreased excretion/increased loss if PU
Problem with ACEi in AKI?
Afferent arteriole vasoconstriction
What AKI cause has best outcome?
Obstructive in cats, toxic and other = worst
Ischaemia = better px
How often does azotaemia persist after AKI?
Around half
Distribution of types of CKD dogs and cats?
Dog - 60 % tubuloint, quarter glomerular, rest amyloidosis/other
Cat - three quarters tubuloint, 15 % glomerular, rest lymphoma/amyloidosis
How does the failing kidney adapt?
Increased load per nephron, increased tubular secretion to maintain electrolyte and water excretion.
Maintained better for Na/K/water than phosphate
Organic solutes
Mediators of uraemia - accumulate as can’t be secreted when GFR starts to fall.
Inhibit NaKATPase, alter platelet, red cell and white cell function
NB as kidney fails can’t catabolise compounds like PTH and cytokines. PTH is a uraemic toxin
Uraemic gastric changes in dogs and cats?
Dogs - can get uraemic gastropathy with ulceration
Cats - fibrosis, gland atrophy, mineralisation in stage III/IV, no evidence ulceration,
Gastric hyperacidity not documented
Halliitosis in renal dz?
Bacterial urease converts urea to ammonia
Enterocolitis in renal dz?
Ammonia produced in colon is irritant
What mediates impaired urine concentrating ability in CKD
Impaired genesis of concentrating gradient due to medullary architecture disruption/countercurrent multiple disruption
Impaired response to ADH (uraemia), increased distal tubular flow rate
What is the most common cause of secondary hypertension?
CKD
Renin, sodium/water retention
Aldosterone and SNS imp
Factors causing anaemia in renal disease?
EPO - decreased production and decreased efficacy d/t nutrient deficiency and uraemic factors
Blood loss (GI, thrombocytopathy)
Inflammation
Decreased RBC lifespan
What does hypoxia inducible factor do?
Increases EPO production and intestinal iron uptake
What does FGF23 do?
Causes phosphate excretion
Inhibits 1alpha hydroxylase
FGF/klotho system
Renal secondary hyperparathyroidism?
Phosphate retention, PTH, FGF23, 1alphahydroxylase inhibition
Decreased calcitriol, decreased neg feedback, increase PTH. Initially calcitriol production is increased to normal at the expense of persistent increases in PTH
CKD progression decreases amount of viable renal cells and more calcitriol deficiency
Calcitriol deficiency impairs bone response to PTH and elevates the set point for PTH so continues to be secreted despite normal or increased calcium.
Uraemic toxins impact PTH response to calcitriol
50 % cats advanced CKD hypocalcaemic.
May get inc PTH prior to azotaemia
RSHP majority cats with CKD and corr with creatinine
Metabolic acidosis in CKD?
Decreased GFR, can’t get rid of daily acid load, no filtration phosphate/sulphate products, impaired tubular proton excretion
Nephrons compensate by increasing ammonium secretion. Structural damage impairs renal ammonium production.,
Retention of organic acids increases the anion gap
Stimulates branched AA degradation - catabolism of muscle
What does urea correlate with?
Uraemic toxins
When does SDMA increase?
Decreased GFR by 25 - 40 %
17/10m earlier than creatinine on cat/dog
IRIS staging categories
I - dog < 125 cat < 140 SDMA < 18 both
II - dog < 250 cat < 250 SDMA dog < 35 cat < 25
III - dog and cat < 440 SDMA dog < 54 cat < 38
IV > 440 > 54 > 38
Proteinuria - dog 0.2 - 0.5/>0.5, cat 0.2 - 0.4/>0.4
BP: <140. 140 - 159, 160 - 179, > 180
Breed spec - 10/10-20/20-40/>40 inc from RI
Sighthound blood pressure?
40 mmHg higher
Phosphate restriction CKD?
Stage II onwards dog and cat - slow progression, decrease RSHP, decrease mortality
I < 1.45
II < 1.45
III < 1.61
IV < 1.94
Diet 4-6 w then add binder
Diet can be effective alone in II and III
Diet in CKD?
Renal diets evidence stage III onwards (maybe II cats?) - increase survival time decrease risk renal death decrease risk uraemic complications. Maintain QoL and decrease clin signs. Decrease phosphate decrease PTH decrease FGF23 in stage II - IV cats. Rec all proteinuric dogs.
Protein restriction - decreases glomerular protein loss which is detrimental to tubules
Controversial otherwise.
Restrict in stage III/IV, decrease urea and uraemia.
But renal diets not restricted enough to cause protein malnutrition if consumption adequate.
Omega 3 - decrease mortality, improve renal function, decrease renal lesions/proteinuria/cholesterol, favourable lipid metab, suppress inflammation and coagulation, decrease BP, antiox, may be synergistic with antioxidants to reduce the decrease in GFR
Phosphate restriction - dog and cat stage II onwards, slow progression decrease mortality
Also: B vitamins neutral acid base soluble fibre increased caloric density and potassium supp feline.
Benefit of subq fluids CKD?
Decrease dehydration which can cause AKI, imp appetite/activity/decrease constipation
Hypokalaemia in CKD?
Around 1/3 of stage II and III cats
Might get hyperkalaemic in stage IV
Hypertension and renal mortality?
Risk factor in canine CKD
What factors should be taken into consideration when using amlodipine in CKD?
Make sure BP not < 120, no signs hypotension, creatine doesn’t increase > 45 or SDMA >2
Development of EPO ABs?
30 % cats 50 % dogs (not all anaemic) when tx epoietin
less darbo
When to use rhEPO?
Stage III onwards, PCV < 22 % with clin signs anaemia
Half to all cats reach target (bottom end RI), responders live longer
Aim 1 - 3 % increase per week
Calcitriol use in CKD?
Decreases PTH
Decreases mortality in canine stage III and IV by slowing progression - cats maybe not so much (?improve podocyte viability and decrease RAAS?)
Use in canine III onward (? II?) with normal phosphate. and iCa
Give fasted to minimise. increase in Ca and phosphate
Make sure calcium phosphorous product <52
Proteinuria and CKD?
Every 1 increase UPCR increases risk of death/uraemic crisis 1.5 x in dogs
Benazepril assoc with survival benefit in cats if UPCR > 1
Intervene if stage I > 2 or stage II onwards > 0.4/0.5
ACE escape?
Chymase enzymes
Bradykinin also degraded by ACE - vasodilation and renoprotection via NO stim
ARB mech?
Block type 1 not 2 - latter imp for vasodilation
Aldosterone blockers?
Attenuates renal damage independent. of BP
Aldosterone might be fibrogenic in kidney (TGFbeta)
Prognostic factors feline CKD?
Stage (1000, 700 and 30d for II - IV)
Phosphorous, proteinuria, anaemia (?), weight loss
NOT nephrolithiasis NOT BP
Prognostic factors canine CKD?
Stage (2.6/4.7 X risk death stage III and IV) BUN Creatinine if no renal diet fed Diet (stage III 250 d vs 600 d) Proteinuria - clin signs, uraemia, death, every 1 UPCR increases death risk 60 % Increased BCS longer survival BP Cause - hereditary slower
HMWP in AKI?
Higher ratio of HMWP to albumin could indicate more severe glomerular injury
Urinary retinol binding protein?
Marker of tubular damage
Why are urinary enzymes more sensitive than protein?
Increased before overt dysfunction
Also, easier to measure and amount of leaked enzymes might be predictive of degree of ongoing damage
Overhydration and AKI?
Might be prognostic (worse disease) or may worsen outcome
Most common glomerular diseases in dogs?
Immune complex glomerulonephritis, glomerulosclerosis, amyloidosis
Signalment of dogs with nephrotic syndrome?
Younger
What glomerular diseases have what USG?
Normal common in general, amyloidosis more frequent isosthenuria
Most common cast in glomerular disease?
Hyaline - Tamm Horsfall mucoprotein secreted due to proteinuria
Membranoproliferative glomerulonephritis?
Immune complex glomerulonephritis
Most severe clin signs and clin path changes
BMD - mesnagiocapillary, familial, auto recessive - asco with lyme dz
Immune complex deposition subendothrlial GBM, cytokine complement activation (NB congenital C3 deficiency in Brittany sp)
C3 IgG/M/A deposition
If can’t fix with address underlying dz consider immunosupp
Membranous nephropathy?
Most common feline, NB young dobermann
Immune complex glomerulonephritis
AB deposition sub epithelial GBM, less complement/cytokine activation
Primary - immune mediated, ABs interact with podocyte antigens
Also secondary - circulating immune complex
Progresses through stages - spikes, GBM thickening and projections surround the immune complexes, bearded appearance due to immune complex deposition
May not have GBM thickening in later stages
Px - later stages poor, C3/IgG better than IgM/A, may be slowly progressive
Immune supp if progressive and no dz to manage
Proliferative glomerulonephritis?
ICGM
Milder
Less likely to be caused by infectious. dz
Mesangial hyperplasia with mononuclear infiltrate
IgG/M GBM or mesangium or cap walls
Immunesupp if no dz and prog
Immunoglobulin A nephropathy?
Enteric/hepatic dz
IgA - polymeric, nonspecific trapping in mesangium
increased formation/decreased clearance
Can also have less intense IgG/M/C3
Amyloidosis?
Familial breeds?
Sharpei, beagle, foxhound, Abyssinian, siamese
More medulla in cats and shar pei, otherwise glomerular dep
Other dogs chronic inflamm - collie, female, walker hounds
Beta pleated amyloid
Don’t need TEM
Colchicine may be helpful in deposition face (decreased SAA release from hepatocytes?)
DMSO maybe in deposition phase? Decrease SAA conc? Anti-inflamm/decrease interstitial fibrosis?
Hereditary nephritis?
ECS/ESS auto rec
Bull terrier/Dalm auto dom
Samoyed one fam X link dom
Type 4 collagen defect causes GBM deterioration (5. in samoyed)
Samoyed males v severely affected
ECS proteinuria from a few months.
Both terminal CKD < 2y
BT/Dal more variable
Need TEM to dx - splitting and fragmentation of GBM
Minimal change glomerular disease?
Masitinib
Rare in dog and cat
Human - lymphokine dysfunctional T cell increase GBM, perm, dx TEM, response steroid
Glomerulosclerosis?
20 % dogs end stage lesion
DM? Hypertensive damage?
Non spec Ig/C3 trapping
Focal segmental glomerulosclerosis = primary dz
How many dogs with glomerular disease have a secondary cause?
Just over half
Target protein in glomerular dz?
< 0.5 or 50 % decrease
Decrease dose or stop if creat increases > 30 % or to stage 4, K > 6.5 or BP < 120
Other tx?
Thromboxane synthase inhibitor may decrease proteinuria, decrease glomerular inflammation
Omega 3 - renoprotective, decrease BP, decrease trig/chol
How many immune mediated glomerular disease in dogs?
Half
When to use immunosuppression in glomerular disease?
Biopsy evidence immune mediated - subepi/endothelial, intramembranous or mesangial electron dense deposits, immunofluorescent staining for immunoglobulin or complement with anti-GBM pattern
No response standard tx
Steroids and glomerular disease?
Use short term, as steroid excess induces glomerular lesions
Myco/ciclosporin considered
Ciclosporin only one prospective (wasn’t found to be of benefit…)
Use immune supp 8-12w before change
If response, use 3-4 m then taper
When to recheck glomerular disease dogs?
Stable stage I/II 3 - 14 d
Unstable or III 3-5d
No need to rebx, changes don’t necessarily resolve
Albumin and hypercoag?
Albumin binds arachidonic acid - if free may get increased platelet aggregation
Hypercoagulability in glomerular dz?
Less alb and AT
More fibrinogen, cholesterol, procoag cytokines, alpha2macroglobulins, alpha 2 antiplasmin
Hyperlipidaemia and glomerular dz?
LDL/oxLDL alter mesangial cell function, increase matrix synthesis and cause glomerulosclerosiss
Lipoprotein deposition is cytotoxic
Prognostic factors glomerular disease?
Azotaemia
Type - GN and amyloidosis worst
Nephrotic syndrome
Cystinuria breeds and causes?
Newfie and lab type 1 - SLc3a1 (rBAT protein) autosomal recessive
Aussie cattle dog - SLc3a1 auto dom incomplete pen (non-type 1)
Min Pin - SLc7a9 - bo+ AT protein
Eng bulldog, rottie, SBT, JRT, welsh corgi, chih, dachs
Form calculus 5 y, newfie/lab younger
Type III = androgen dependent
Cats described
Cysteine, carnitine fail to resorb NB cardiac
Management cysteineuria?
Alkalinising diet
Low protein
Diuresis
2 - mercaptopropionylglycine
Breeds and cause hyperuricosuria?
Dalmatian - can’t move uric acid into hepatic cells, impaired PCT uric acid absorption, active urate excretion DCT. Slc2a9 - auto recessive, all dals have mutation
English bulldog, Black Russian terrier Slc2a9, auto rec
Primary hepatic dz
Cats PSS and idiopathic
NB neoplasia HAC CKD
Management of hyperuricosuria?
Allopurinol, xanthine oxidase inhibitor
Purine restricted diet, alkalinising to decrease tubular ammonia
Medical dissolution in PSS if fix
Breeds and cause of hyperxanthinuria?
Allopurinol tx
CCKS wire-haired dachs
Cats
Decreased xanthine oxidase activity
Breeds for primary renal glucosuria?
Basenji, scottie, Norwegian elkhound
How many Basenjis get Fanconi?
10 - 30 %
Causes of acquired Fanconi?
Gentamicin, hypoparathyroidism, tubular necrosis
Chlorambucil cats
Jerky treats
Common amino acid in urine of Fanconi?
Cysteine
What is lost from tubules in Fanconi?
AAs glucose bicarb sodium potassium urate uric acid phosphate
What acid base disturbance do Fanconi dogs get?
Hyperchloraemic (nonAG) metabolic acidosis (bicarb loss)
How to manage Fanconi?
Potassium citrate, aim bicarb 18 - 24 K 4 - 6
Prognosis Fanconi?
Good - MST 5 y (and some don’t present until 4-8y). most good/excellent qol. 50 % die reasons unrelated
Type I renal tubular acidosis?
Distal tubular acidosis
Failure excrete H+
Hyperchloraemic metabolic acidosis, severe acidosis, urine pH > 6
Hypercalciuria, hyperphosphaturia
More severe bone dz and nephrocalcinosis poss, urolithiasis poss
Can have severe hypoK
No PCT defects
Good response to alkali tx and don’t need as much
Low bicarb excretion
Urine pH > 6 in acidaemia and if give ammonium chloride
Citrate in urine decreased
NB: pyelonephritis cats and lepto dogs
Type II renal tubular acidosis?
Proximal tubular acidosis
Failure to prevent bicarb loss (DCT compensates)
Basolateral Na-bicarb cotransporter defect, bicarb leaks to tubular lumen
Hyperchloraemic MA (less severe)
Other tubular defects poss
Need large amount of alkali tx and less good response - marked bicarbonaturia with increased pH and increased fractional excretion of bicarb
Urine pH acidic and decreased with ammonium chloride challenge
Less clin consequences eg bone, no nephrocalcinosis and urolithiasis unusual
Still have calcium and phosphate in urine
Type IV renal tubular acidosis?
Hypoaldosteronism/aldosterone antagonism
Loss HATPase stim, decreased distal sodium absorb
Hyperchlor MA and increased K
High and intermediate molecular weight protein used for acute tubular injury?
Systemic circulation
Albumin - glomerular/prox tubule - non specific
Immunoglobulin IgA/G - glomerular, no advantage over UPCR
Low molecular weight protein used for acute tubular injury?
From PCT or systemic circ and decreased resorption
Retinol binding protein - from prox tubule, stable in acidic urine and frozen, increases progressively in CKD, wide interindividual variation
Alpha 1 microglobulin - stable in acidic urine, decreased in hepatic disease
Beta 2 microglobulin - UNSTABLE acidic urine - predictor GFR in dogs but not sensitive enough to monitor progression
Tubular enzymes used in acute tubular injury dx?
Large molecules expressed in urine from damaged tubular cells and increased before overt dysfunction. May predict degree/severity of injury?
Neutrophil gelatinise associated lipocalin - PROX tubule only, haematuria/pyuria interfere and infection or inflammation decreases specificity. Is freeze/thaw stable.
Lactate dehydrogenase - PROX tubule
Gamma glutamyl transferase - PROX tubule, UNSTABLE in acidic urine. Haemorrhage and pyuria interfere
N acetyl D glucosaminidase - prox and distal affected by HT4/DM, pyuria and storage
Intestinal ALP - prox and distal
Breeds predisposed to renal agenesis?
Beagle, doberman, sheltie
Breeds for renal dysplasia?
Lhasa/shih tzu, SCWT, Gret, Boxer
AUS renal dysplasia?
Loss corticomedullary definition, hyper echoic speckles
Histopath renal dysplasia?
Inappropriate differentiation of nephron components - immature alongside mature
Functional nephrons hypertrophied
Podocytopathy?
SCWT NPH1/KIRREL2 genes (split diaphragm proteins nephrin neph5 filtrin)
Polycystic kidney dz breeds and cause?
Persian and crosses, auto dominant PKD1 (polycystin) gene mutation - also Himalayan and British blue. Probably other mutations too as described in absence of this mutation.
Bull terrier - auto dominant PKD1 gene mutation
Cairn/WHWT auto recessive PKD1- get liver cysts too
Cystadenocarcinoma?
GSD, auto dom mutation, BHD gene
False neg protein dipstick?
Bence Jones acid dilute, quite sensitive overall though for albumin
Also poor specificity
What does the sulfosalicylic acid test check for?
Bence jones proteins and globulins
Poor sens and spec for albumin
Physiological proteinuria?
Stress, exercise, seizures, hyperthermia
Pre-renal proteinuria?
Bence jones
Postrenal?
Cysto help but prostatic secretion can reflux
How is persistent proteinuria defined?
Three or more tests more than 2w apart.
NB proteinuria may decrease as renal dz progresses (less nephrons)
When is protein change significant?
35 % at UPCR 12, 80 % at 0.5
Need to pool 3 if > 4
When should proteinuria be treated?
No renal dz - > 1
Renal dz stage 1 onwards - > 0.4/0.5
What effect does enalapril have on glomerular disease?
Sig decrease proteinuria, delay onset and progression of azotaemia
Why might potassium be high in glomerular disease?
ACEi/ARB
Pseudohyperkalaemia d/t thrombocytosis
Why less cell response in membranous glomerulonephropathy?
immune complex dep not endothelial, is sub epithelial GBM
Difference between familial and reactive amyloidosis?
Familial Abyssinian shar pei medullary mostly some glomerular, reactive all glomerular
What colloid to use in nephrotic syndrome?
Not colloids - HMW molecules lost quickly and leave high sodium fluid behind, increasing hydrostatic pressure
Use plasma or human albumin
When to give aspirin in glomerular disease?
< 20 g/l albumin
When to use bicarb/citrate in CKD?
Cat bicarb < 16 dog < 18
Most common NSAID nephrotoxicity?
Acute cortical nephrotoxicity, chronic medullary cytotoxicity less common
Doesn’t differ selective/non-selective
General risk factors for renal NSAID tox?
Dehydration Hypotension Admin of anti-hypertensives which are not renal vasodilators Higher NSAID dose Hypoalbuminaemia Genetic? GSD?
Only risk factor for acute cortical NSAID nephrotox?
Dietary salt restriction, diuretic, GA
Pathophys of the NSAID nephrotox’s?
Acute cortical nephrotox:
Loss renoprotective effects vasodilatory prostaglandins. Decreased renal blood flow/GFR Cox 1 > cox 2
Chronic medullary cytotoxic:
Loss cytoprotective prostanoids. Medullar interstitial/tubular cell papillary necrosis Cox 2 > Cox 1
Clin findings NSAID nephrotox?
Acute cortical nephrotox:
Early: Renal cells/casts in urine, renal enzymuria, proteinuria, microalbuminuria
Intermediate - electrolytes abnormal, decreased conc
Late - creatinine
Chronic medullary cytotoxic:
No early
Intermediate - renal enzymuria, decreased conc ability
Late - electrolytes, acid base, creatinine
What factors may be problematic when using NSAIDs in CKD?
Hypoalbuminaemia (protein bound)
Metabolites might be renally excreted
Low reserve so damage may be disastrous
NB cat CKD NSAID slowed progression… low dose 0.01-0.03
Use sub therapeutic dose at first, titrate up, and use in bursts rather than continuously
When does risk of UTI increase with indwelling ucath?
3d onwards
Furosemide and diuresis?
CRI more effective cf intermittent bolus
Dopamine agonists for diuresis?
Dopamine itself not recommended
Fenaldopam D1 receptor antagonist, renoprotective in people - might be effective? Monitor for hypotension
How to give amlodipine if you can’t give it orally?
Rectally
Negative prognostic indicators AKI?
Ethylene glycol and azotaemia
Severe azotaemia
No imp/worsening despite tx
Concurrent dz eg pancreatitis, sepsis
What marker of renal function has least within individual variability in azotaemic cats?
Creatinine, better than GFR
What does high phosphate diet do to healthy cats?
Glucosuria and microalbuminuria and decreased creatinine clearance in the short term
What happens to magnesium in CKD cats administered gastroprotectants?
Decrease over time with combined PPI H2 blocker
Also increased sodium PPI
No increase in CKD progression though
What is subclinical bacteriuria associated with in cats?
Uncommon - 6% Most single organism (E coli) More likely female Assoc with bacteriuria and pyuria Assoc with low USG and CKD Hepatic disease
NAG in feline idiopathic cystitis?
N-acetyl beta D glucosaminidase:
NAG/creatinine higher in FIC - > degrade GAG? Is in tubules (PCT) and can degrade glycoprotein and mucopolysaccharide
UPCR higher too
UPCR corr with NAG
CKD risk factors cat?
Feeding commercial dry food PROTECTIVE
Periodontal dz increased risk
Feline familial amyloidosis?
Oriental/siamese - mainly liver -
Abyssinian/somali - renal, die young
Difference between - ? different kind of amyloid?
Glomerular proteinuria in cats?
Young male with higher proteinuria
Immune mediated dz common
ICGN: live longer if get immunosuppressive, effusion neg prog
75 % immune complex mediated
Membranous glomerulonephritis most common
Poor px overall
FGF 23 in canine CKD?
Increased in stage 2-4 cf 1 and corr with stage
Corr with increased phosphate
More stage 2 have increased FGF23 cf PTH
PTH, creatinine and phosphate predict FGF23
Correlated with survival
What is FGF23?
Phosphotonin. Released from osteocytes when phosphate and calcitriol increased, increases urinary phosphate excretion by decreasing sodium phosphate cotranssporter
Inhibits calcitriol
As CKD progresses, less alpha klotho (cofactor)
Binds to FGF receptor
Cat CKD and FGF23?
Increased earlier than phosphorous or PTH, neg px indicator
Corr with low magnesium, magnesium corr with risk of death
Corr SDMA and creat, increased in non-azotaemic but SDMA inc cats
Bacteria and disease progression feline CKD?
No effect positive urine culture if treat with ABs
PUC around 22 % CKD cat
Most no clin signs
Telmisartan in proteinuria in dogs?
Probably more effective than enalapril
Combo might cause azotaemia
Predictor of short term outcome in acute on chronic AKI?
AKI grade
Vitamin D in PLN?
Decreased in non-azotaemic - corr with amount of protein loss and with decreased albumin
Decreased vitD binding protein as albumin decreased
Risk factors for enterococcal bacteriuria in dogs?
Recurrent bacteriuria, anatomical abnormalities, urolithiasis, neoplasia
Is this bacteria a marker of concurrent dz?
Glucosuria and USG?
Not actually that much change
What confers fluoroquinolone resistance?
DNA gyrase/topoisomerase genetic mutations in bacteria
Blood in urine and UPCR?
Microscopic might effect UPCR
Platelet changes in CKD dogs?
Hypercoag.
Increased alpha IIb beta 3 and P-selectin
Experimentally, what may accelerate renal regeneration after AKI?
Autologous bone marrow derived mesenchymal stem cells, GCSF (latter decrease fibrosis)
Cranberry extract and canine UTI?
Prevented UTI
Prevent E coli kidney cell adherence in vitro
In another study not better than placebo
Recurrence in feline urinary obstructions?
No difference any outcome measure for saline lavage
Less if indwelling
Meloxicam didn’t help
Intravesicular pentosan polysulfate didn’t help
How many SUBS cats survive to discharge?
94 %
Prevalence bacteriuria CKD dog?
Not assoc stage
Around 20 %
Sub clin then pyelonephritis then cystitis most common
How to maximise renal bx yield?
16 g, US guided
Stent vs SUBS cat?
Mortality more, survival less, hosp more, complication more in stent
Stent lower urinary signs and get infected more
Calcium oxalate urolithiasis and weight?
More in fat dogs
Amoxicillin and feline kidney disease?
Amoxicillin decreased in urine of azotaemic cats, may be inc in serum
? SEs?
Mirtazapine in CKD
Transdermal works to increase appetite and weight
Troponin I in renal disease?
Increased in serum same as cardiac
Increased in urine more than cardiac
Cats
Categories for bacteriuria?
Sporadic cystitis (< 3 in a year)
Recurrent cystitis (3+ in a year or 2+ in 6m) - relapse/reinfection/persistence/superinfection
Pyelonephritis - acute uncomplicated/complication, chronic
Subclin bacteriuria - no clin signe
Bacteriuria with implant or ucath
UTI in FLUTD?
Low prevalence (3 - 19 %) in young but. up to 45 % in > 10y
Prevalence pos urine cultures cats diff dz?
CKD up to 30 %, DM/HT4 around 13 %
Clin signs more common latter two?
Pos in 30 % ureteral obstruction, also SUBS infections reach 30 %
Where does KIM1 live?
Kidney injury molecule - prox tubule - increased in sepsis/urethral obstruction
Cat breed with higher creatinine?
Birman
Homocysteine/CKD?
Uraemic toxin
Dogs:
Increased if decreased renal excretion or impaired metabolism
Corr proteinuria
Cats:
Increased and corr with stage/UPCR, not hypertension
NB may not be assoc with cobalamin deficiency in cat
Main difference bacterial cystitis in cats?
Often comorbidity present and far more common older cats
How to treat sporadic UTI?
3-4d amoxicillin or TMPS
Always culture cats
NSAID alone might be enough
This also applies to males with no evidence prostatitis, and comorbidities not affecting utract
This does not apply to recurrent (additional UTI < 3m)
Check culture afterwards not recommended
How to treat recurrent UTI?
Determine relapse/persistence/recurrence
Evaluate for cause
Check AB propriety and compliance
3-5 day for recurrent, longer (7-14) persistent/relapse
NB amoxicillin-clav ineffective against E. coli in tissue
Can reculture during if using longer course/after, but ? change tx if clin signs gone
How to treat pyelonephritis?
Do blood culture if immune supp or fever
Interpret susceptibility with serum/tissue breakpoints not urine
Check lepto if culture neg
Quinolone (efficacious cf e coli)
10 - 14d, recheck culture 1-2w after stop AB but NB ? change tx if clin response
AB for prostatitis?
Weakly alkaline, lipid soluble high pKa ABs
Quinolone or trimethoprim
Chloramphenicol, tetracycline don’t penetrate, and macrolide/clindamycin penetrate but no e coli efficacy so poor choice
How to treat prostatitis?
Always check for in male dog with bacteria in urine
Breakpoints for serum
? aspirate prostate? 100000CFU bacteria might be normal in prostatic wash
Drain abscess
4-6w + castrate, longer chronic
Rpt wash if clin signs remain + consider other ddx
How to manage subclinical bacteriuria?
Not assoc with survival or development of clin signs
Poss treat if high risk ascending inf or if think caused inf elsewhere
Poss treat if can’t show signs (paralysed) with fever or other clin signs - short course 3-5d
Poss treat if plaque/urease forming (Corynebacterium urealyticum or Staph), 3-5d
Risk factors subclinical bacteriuria dog?
DM, obesity, parvo pup, acute disc, paralysed dogs, steroid/ciclosporin
Enteroccous tx?
Need aminoglycoside with ampicillin
Bacteria assoc with struvite?
Staph pseudintermedius, proteus mirabilis
Urolithiasis and AB?
Always culture as could be struvite component
Cats almost all sterile
Culture urine, and urolith if urine neg
AB 7d if signs, if struvite with urease producing bacteria (duration? 7d ab seemed fine in one study)
Urinary heat shock protein 72 in renal dz?
Stress induced cytoprotective protein
Predict survival time CKD cat
Increased in CKD and AKI cat
Sens > spec cat
Dog - same, sens and spec better than cat, sens still > spec. AKI only. Predict survival AKI.
Parvo and AKI?
Increased urinary IgG, CRP, retinol binding protein and neutrophil gelatinise associated lipocalin
Also increased UPCR
Urea/creatinine not increased
Plasma indoxyl sulfate in CKD?
Protein bound uraemic toxin, metabolic breakdown of tryptophan in intestine > indole > hepatic metabolism. Renal tubule excretion. Accum in tubular cells cause progression?
Predicts stage progression in dogs and cats
Cats - assoc with FGF23 (assoc with phosphate metabolism?), strong corr with phosphate
GGT/ALP in AKI?
Urinary - both prox tubule brush border
Poor sens/spec, ALP better than GGT
Urinary IgM/IgG?
Increased in AKI and CKD
More increased in ICGN - also prognostic
Urinary retinol binding protein?
Inefficient tubular absorption
Increased AKI
Increased CKD and prognostic
Higher in proteinuria animals
Urinary NGAL?
Decreased tubular absorption and prox tubular cell damage releases
Gentamicin - early marker and corr with injury
Increased AKI/sepsis
Also increased CKD, glomerular dz, lower utract dz
Active sediment big problem
Increased neoplasia same as CKD
Which urine markers glomerular which tubular?
Tubular - UPCR SDSPAGE albumin NAG clusterin cystatin C GGA KIM NGAL RBP THP
Glomerular - UPCR SDSPAGE albumin CRP Ig NAG NGAL
Urinary N-acetyl beta d glucosaminidase?
Tubular cell lysosomal enzyme - released on damage.
Higher intact males.
AKI/CKD
Corr proteinuria
Sensitive
Glomerular dz (better glomerular?)
Serum cystatin C?
Small protein cf SDMA (which is creatinine sized)
More sens GFR cf creatinine?
Inferior creatinine SDMA for GFR dogs
Urinary active transforming growth factor beta?
Increased 6m pre azotaemia in cats
Predict fibrosis, renal inflamm and UPCR
Also assoc with fibrosis:
Mini schnauz and proteinuria?
Corr trig and UPCR
UPC >0.5 60 % hypertrig cf none normal trig
No azotaemia/hypoalb/hypertension, no cardiac dz, AT3 normal
Lipid induced glomerular injury?
Decreased lipoprotein lipase?
Segmental glomerular sclerosis
Immune supp and glomerular dz?
Mycophenolate +/- chlorambucil - all/6 alive at end of study vs one/7 with no immune supp
ICGN less common in UK? 27 % vs 50 %?
Risk factors urinary incontinence dog?
Early onset (<8y)= neutering and neutering <6m, no impact age of spay in UI overall
Hazard increased with inc bodyweight, Irish setter most hazard breed
Decreased oestrogen, LH/FSH, COX2/gonadotropon receptors?
Increased GAG/collagen?
High risk breeds - Irish setter, doberman, bearded collie, dalmatian
Type III cystinuria?
Androgen dependent - mastiff, staffie, Scottish deerhound, Irish terrier. Entire males.
Grape/raisin tox?
Neuro signs 75 % in a group of AKI not assoc severity outcome etc
Focal segmental glomerulosclerosis?
Non immune complex, podocyte injury, compression of capillary lumen
Females
26 % cases
Severe hypoalb/ascites/oedema and azotaemia uncommon, hypertension frequent
Creatinine and alb assoc with survival
NB SCWT, Airdale, mini schnauz
USMI bulking outcomes?
70 - 100 % effective
Acute on chronic kidney disease cats?
Phosphate assoc short term outcome creatinine long term
Short survival after discharge
Around 60 % discharged
Most common infectious dz exposure proteinuric dogs?
Rickettsia, Ehrlichia, Borrelia
More if alb lower/creatinine higher
Neuroendocrine alterations in FIC cats?
Increased systemic/localised sympathetic
Decreased HPA
increased muscarinic stim response
Feline CKD microbiome?
Decreased diversity.
May increase SCFA
Dysbiosis exacerbates colonic derived uraemic toxins eg indoxyl sulfate and p cresol sulfate
What is beraprost sodium?
Prostacyclin analogue, might help with renal hypoxia/fibrosis
Name urease producing bacteria
Corynebacterium urealyticum, Staph, Klebsiella, Proteus, Mycoplasma
What urinary tract infection bacteria are catalase negative?
Enterococcus/strep
UTI bacteria in dogs/cats?
E coli most common in both
Mostly gram negative dogs, equal gram neg/pos cat
Enterococcus second most common cat
What UTI bacteria express fimbriae?
E coli
Gram neg
Klebsiella pneumoniae
Most common compound urolith?
CaOx inner struvite outer, then struvite inner calcium phosphate outer
Urate stone former mutation?
SLC2A9
Failure reabsorption prox tubule
Secretion DCT
Breeds for feline urate and cysteine stones?
Urate - Egyptian mau, Birman, siamese
Cystine - siamese
Additional amino acids which are deficient with cysteine loss in urine?
Carnitine/taurine dogs
Cats - COLA
What makes up the COLA transporter?
2 heterodimers, RBAT and bo+AT
SLC3A1 and SLC7A9 genes
Deficiency in what vitamin can predispose to calcium oxalate deficiency?
B6 - decreased oxalate metabolism
USMI response for various management options?
Oestrogen: 89 %
Phenylpropanolamine: 75 - 90 % female, 43 % male
Collagen: 60 %, more if add phenylpropanolamine
Artificial sphincter: 90 % medical refractory
Risk factors for FIC?
Overweight, multicat household, fearful behaviour, less outdoor access, decreased water intake
Ectopic ureter morphology?
Dog - male and female most intramural and bilateral
Cat - intramural, equal bilateral/unilateral
Characteristics of bacteria causing UTI?
Fimbriae/pili adhesins
Toxins eg haemolysin
Host immune system evasion eg capsular antigen
Utilise host nutrients eg aerobactin
Uropathogenic E coli B2/D
Risk factors UTI dog/cat?
Dog: Steroids/immunosuppressivess DM Parvo Obesity Chemo
Cat: DM CKD Female HT4?
