31/10/2016

Chronic renal failure in dogs and cats: pathogenesis and diagnosis, survival and treatment Eric Zini PD, PhD, Dipl. ECVIM-CA (Internal Medicine)

Chronic kidney disease 

Irreversible and slowly progressive



Due to: > 3 months

Definition

 Any renal damage  Decreasing GFR > 70%

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Chronic kidney disease 

Irreversible and slowly progressive



Due to:  Any renal damage  Decreasing GFR > 70%

> 3 months

 Markers of renal damage (blood and urine)  Macroscopic  Microscopic

Etiology

Definition

Abnormalities:

Di Bartola

Congenital/hereditary causes

Etiology

 Policystic kidney disease  Amyloidosis  Renal displasia

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Acquired causes

Etiology

 Obstruction  Lymphoma  Hyperthyroidism

Acquired causes

Etiology

 Toxic  Drugs  Infectious

Acquired causes

Etiology

 Toxic  Drugs  Infectious

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Acquired causes

Etiology

 Hypercalcemia

Acquired causes

Etiology

 Hypercalcemia

Acquired causes

Etiology

 Diet: rich in proteins low in potassium

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Acquired causes  Diet and natrium?

Etiology

risk  K+

Etiology

...Often the cause is unknown

Etiology

...Often the cause is unknown

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Pathophysiology

How does the damage progress in the tubular cells?

Pathophysiology

…inflammation

Pathophysiology

…inflammation

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Pathophysiology

...fibrosis

Pathophysiology

...inflammation and fibrosis

Pathophysiology

...fibrosis

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Pathophysiology

...RAAS activation

...RAAS activation

Pathophysiology

Angiotensin II

TGF-β1

Fibrosis

Vasoconstriction aff./eff. arteries

Proteinuria and glomerular damage

Aldosterone

Na+/K+

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...RAAS activation

Pathophysiology

Aldosterone

TGF-β1

ROS

Inflammation

Loss of podocytes

Proteinuria and glomerular damage

Fibrosis

Pathophysiology

...and in cats?

...RAAS activation

Pathophysiology

Am J Vet Res. 1997 May;58(5):535-40. Plasma renin activity and angiotensin I and aldosterone concentrations in cats with hypertension associated with chronic renal disease. Jensen J, Henik RA, Brownfield M, Armstrong J.

Nephropathic-hypertensive cats • = renin, angiotensin I •  aldosterone

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...RAAS activation

Pathophysiology

J Vet Med Sci. 1998 Jul;60(7):805-8. Non-invasive blood pressure measurements in cats: clinical significance of hypertension associated with chronic renal failure. Mishina M, Watanabe T, Fujii K, Maeda H, Wakao Y, Takahashi M.

Nephropathic cats •  renin •  angiotensin I and II •  aldosterone

Pathophysiology

...RAAS activation

Pathophysiology

...”ACE escape”???

ACEi suppresses ACE... however later on aldosterone   are there alternative pathways to convert angiotensin I in II???

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Pathophysiology

...”ACE escape”???

in cats, chymase pathway J Vet Med Sci. 2003 Oct;65(10):1115-8. Angiotensin converting enzyme and chymase activity in the feline heart and serum. Aramaki Y, Uechi M, Takase K.

Pathophysiology

...and in dogs?

Pathophysiology

...RAAS activation

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Pathophysiology

...”ACE escape”???

Am J Vet Res. 1996 Nov;57(11):1645-52. Effects of long-term treatment with enalapril or hydralazine on the renin-angiotensin-aldosterone system and fluid balance in dogs with naturally acquired mitral valve regurgitation. Häggström J, Hansson K, Karlberg BE, Kvart C, Madej A, Olsson K.

ACEi suppresses ACE... however later on aldosterone   are there alternative pathways to convert angiotensin I in II???

Pathophysiology

What is the role of proteinuria?

Pathophysiology

...proteinuria

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Pathophysiology

...proteinuria

? 13

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...proteinuria

UPC 1.0 uremic crisis

survival

Clinical signs

Clinical signs

Pathophysiology



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Diagnostic work-up

Diagnostic work-up Clinical signs

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Staging

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IRIS CREATININE (mg/dl) DOG

CAT

STAGE 1

< 1,4

< 1,6

STAGE 2

1,4 -2

1,6-2,8

STAGE 3

2,1-5

2,9-5

STAGE 4

>5

>5

Systolic Pressure (mm Hg)

Staging

UPC DOG

CAT

non proteinuric

< 0,2

< 0,2

border-line

0,2-0,5 0,2-0,4

proteinuric

> 0,5

> 0,4

DOG and CAT No risk

< 150

Minimal risk

150-160

Moderate risk

160-170

High risk

> 180

STAGE 1 and 2 CREATININE (mg/dl) DOG

CAT

STAGE 1

< 1,4

< 1,6

STAGE 2

1,4 -2

1,6-2,8

STAGE 3

2,1-5

2,9-5

STAGE 4

>5

>5

Staging

Stage 1  no clinical signs or PU/PD

STABLE

Stage 2  body weight loss, disorexia

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STAGE 3 and 4 CREATININE (mg/dl) DOG

CAT

STAGE 1

< 1,4

< 1,6

STAGE 2

1,4 -2

1,6-2,8

STAGE 3

2,1-5

2,9-5

STAGE 4

>5

>5

Staging

Stage 3  symptomatic, if treated no uremia

PROGRESSIVE

Stage 4  often uremic syndrome

Clinical use



Median survival time (days):

Staging

STAGE

MST (from diagnosis)

MST (post fluids)

1

-

-

2

1151

1151

3

778

679

4

103

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Staging

Clinical use

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www.mp.blogs.com

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IRIS: WHAT’S NEW? CREATININE (mg/dl) CAT

STAGE 1

< 1,4

< 1,6

STAGE 2

1,4 -2

1,6-2,8

STAGE 3

2,1-5

2,9-5

STAGE 4

>5

>5

Staging

DOG

IRIS: WHAT’S NEW?

Staging

CREATININE (mg/dl) DOG

CAT

STAGE 1

< 1,4

< 1,6

STAGE 2

1,4 -2

1,6-2,8

STAGE 3

2,1-5

2,9-5

STAGE 4

>5

>5

...SYMMETRIC DIMETHYLARGININE (SDMA)

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...SYMMETRIC DIMETHYLARGININE (SDMA)

SDMA

• Arginine is methylated in all cells

L-arginine

SDMA

...SYMMETRIC DIMETHYLARGININE (SDMA) • Arginine is methylated in all cells • Proteins containing methylated arginine,

SDMA

catabolized in: monomethyl-arg asymmetric dimethyl-arg SDMA

...SYMMETRIC DIMETHYLARGININE (SDMA) • Arginine is methylated in all cells • Proteins containing methylated arginine, catabolized in: monomethyl-arg asymmetric dimethyl-arg SDMA

SDMA

• SDMA > 90% renal excretion... early  GFR,  SDMA

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SDMA in cats • Strong correlation with GFR • Increases months-years before creatinine

SDMA

• Not affected by muscular mass

SDMA in dogs • Strong correlation with GFR • Increases months-years before creatinine • Not affected by muscular mass

SDMA

• > in large-breed dogs

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IRIS staging: in light of SDMA?

CREATININE (mg/dl) DOG

CAT

STAGE 1

< 1,4

< 1,6

STAGE 2

1,4 -2

1,6-2,8

STAGE 3

2,1-5

2,9-5

STAGE 4

>5

>5

IRIS staging: in light of SDMA?

CREATININE (mg/dl) DOG

CAT

STAGE 1

< 1,4

< 1,6

STAGE 2

1,4 -2

1,6-2,8

STAGE 3

2,1-5

2,9-5

STAGE 4

>5

>5

Questions

...if SDMA  14 μg/dl: it is STAGE 1 ...if SDMA  25 μg/dl: from STAGE 2 to 3 ...if SDMA  45 μg/dl: from STAGE 3 to 4

Di Bartola

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Is the development of the disease predictable?



When does the disease worsen?



What about survival?



How to treat?



Is the development of the disease predictable?

Risk factors

Questions



Di Bartola

Risk factors

Age

Lulich JP et al. Compend Contin Edu Pract Vet 1992; 14: 127-152

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Breed

◦ Siamese ◦ Abyssinian

Risk factors

◦ Persian ◦ Maine Coon ◦ Burmese

Breed

◦ Shar-pei ◦ Cocker

Risk factors

◦ Golden retriever ◦ Boxer ◦ Beagle

...juvenile nephropathies

Breed

◦ (Shar-pei) ◦ Cocker ◦ Golden retriever ◦ Boxer ◦ Beagle Renal dysplasia

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Risk factors

Risk factors

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

Old healthy cats according to owner, included if normal creatinine



Follow-up of 12 months



Age at T=0: 12.6 years (11.0-14.4)



Old healthy cats according to owner, included if normal creatinine



Follow-up of 12 months



Age at T=0: 12.6 years (11.0-14.4)   creatinine in 30.5% within 12 months



Cats with  creatinine within 12 months, vs. those that did not show  creatinine, at T=0 had: ◦ creatinine >

Risk factors

◦ proteinuria >

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

Cats with  creatinine within 12 months, vs. those that did not show  creatinine, at T=0 had: ◦ creatinine >

Risk factors

◦ proteinuria >  Creatinine and proteinuria are risk factors

Hypertensive cats at T=0, 12.7%



Among hypertensive cats at T=0, 38.5% has  creatinine within 12 months



Hypertensive cats at T=0, 12.7%



Among hypertensive cats at T=0, 38.5% has  creatinine within 12 months

Risk factors

Risk factors



 Hypertension is not a risk factor

risk factor if not treated?

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Risk factors

HYPERTENSION

The frequency of renal lesions is similar between hypertensive and not hypertensive

Risk factors

HYPERTENSION

The frequency of renal lesions is similar between hypertensive and not hypertensive  Hypertension is not associated with histopathologic lesions

risk factor if not treated?

....else to consider?

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Risk factors

Risk factors

....else to consider?

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HYPERTENSION

Risk factors

SAP between 160 and 210 mm Hg

risk factor even if treated

When does the disease worsen?

Questions



Nephropathic cats



Progression: 25%  creatinine



Cats followed-up until  STAGE or for 1 year

Progression



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Nephropathic cats



Progression: 25%  creatinine



Cats followed-up until  STAGE or for 1 year

Progression



Stage 4

IRIS staging!

Stage 3

Stage 2

%

Risk factors Proteinuria ◦ UPC increase of 0.1  risk +24%



Phosphate ◦ increase of 1 mg/dl  risk +41%



Anemia ◦ PCV decrease of 1%  risk +10%



Worsening of proteinuria

Progression

Progression



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Questions

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What about survival?

Prognosis

Questions



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Median survival time (days):



Prognosis

STAGE



MST (from diagnosis)

MST (post fluids)

1

-

-

2

1151

1151

3

778

679

4

103

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Negative prognostic factors: ◦  age ◦  creatininemia

Prognosis

◦  phosphatemia ◦  proteinuria ◦  PCV ◦  leukocytes

Prognosis

Hypertension and urinary infections are NOT negative prognostic factors

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 creatininemia (IRIS Stage)



 urea



Proteinuria



Hypertension

Prognosis

Prognosis

Prognosis



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Prognosis

Prognosis

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

BCS (1-3)



Hypoalbuminemia



phosphate and  PTH

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Questions

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

How to treat?

DIET 

Important: ◦  uremic crises ◦  survival time (up to 100-200%) IMPORTANT POINTS

Treatment

LOW in:

RICH in:

proteins

potassium

phosphate

omega 3

natrium ?

fat

J Small Anim Pract. 2000;41(6):235-42. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. Elliott J, Rawlings JM, Markwell PJ, Barber PJ. J Am Vet Med Assoc. 2002;220:1163-1170. Clinical evaluation of dietary modification for treatment of spontaneous chronic renal failure in dogs. Jacob F, Polzin DJ, Osborne CA, Allen TA, Kirk CA, Neaton JD, Lekcharoensuk C, Swanson L.

DIET 

Important: ◦  uremic crises ◦  survival time (up to 100-200%) IMPORTANT POINTS

Treatment

LOW in:



RICH in:

proteins

potassium

phosphate

omega 3

natrium ?

fat

Effect: ◦  phosphate and urea ◦ preventing  PTH ◦ ...IRIS Stage 2

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DIET

Treatment

! DIET

Treatment

And if does not want it???

DIET And if does not want it??? Slow introduction  Home diet? ...often not balanced 

Treatment

JAVMA 240(5);532-8, 2012

 

Senior diet + phophate binders Warm it

 Add

it with salt?

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DIET And if does not want it???



Mirtazapine ◦ appetite stimulant ◦ antiemetic 5-HT3

Treatment

◦  in nephropathic cats

DECREASE PHOSPHATE

 

STAGE 2 and 3  renal diet enough STAGE 4  binders (e.g., alkalinizers, chitosan)

Treatment

IRIS TARGET (mg/dl)



STAGE 2

2,5 - 4,5

STAGE 3

2,5 - 5

STAGE 4

2,5 - 6

Binders: ◦ With food ◦ Food aversion

Treatment

BINDERS ...AND “EVIDENCE BASED MEDICINE”?

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Treatment

BINDERS ...AND “EVIDENCE BASED MEDICINE”?

BINDERS

Berl Munch Tierarztl Wochenschr. 2004;117:310-315. Effects of a dietary chitosan and calcium supplement on Ca and P metabolism in cats. Wagner E, Schwendenwein I, Zentek J.

Treatment

...in cats with CKD calcium carbonate and chitosan decreased plasma urea and inorganic phosphate after 35 days of treatment

Treatment

BINDERS



Ca-carbonate, K-citrate and chitosan

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BINDERS

Treatment

Included

BINDERS

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Treatment

Control (15)

Treatment (16)

Renal Diet T0

T4-8

T16-20

T44

BINDERS

Treatment

GROUP

IRIS Stage 2

IRIS Stage 3

IRIS Stage 4

Total dogs

Control

4

4

7

15

Treatment

2

4

10

16

Mean Serum Creatinine (mg/dL) C=5.7; T=4.9 p > 0.05

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BINDERS



Ca-carbonate, K-citrate and chitosan

Treatment

treatment control

Treatment

BINDERS... else???

Treatment

...AND UREMIC TOXIN METABOLIZERS???

...was not useful, but capsules were opened...

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ANTI-HYPERTENSION



Target: < 150 mm Hg



Amlodipine ◦ Rapid onset of action ◦  30-50 mm Hg

Treatment



ACEi (benazepril/enalapril) ◦ Slower action ◦  10 mm Hg ◦ Monitor creatinine

DECREASE PROTEINURIA

RAAS Angiotensin II receptor antagonist (AT)

ACEi

Treatment

ATr

NOT if severely dehydrated or if severe chronic kidney disease is present

ACEi



DECREASE PROTEINURIA

61 CKD cats, benazepril vs. placebo, follow-up 6 months

Treatment

◦ UPC: stable vs.  ◦ Creatinine and urea: = ◦ Deceased: 0% vs. 11% ◦ Progression from Stage 2-3 to 4: 73% vs. 93% ◦ Quality of life: 34% vs. 21%

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ACEi



DECREASE PROTEINURIA

192 CKD cats, benazepril vs. placebo, up to 3 years ◦ UPC:  vs. =

◦ Survival: = ◦ Total proteins: stable vs.  ◦ Appetite: improved with benazepril ◦ Side effects: no  K+, no  creatinine

AT

DECREASE PROTEINURIA

AT

DECREASE PROTEINURIA

Treatment

Treatment

◦ Creatinine and urea: =

Treatment

BENAZEPRIL

vs.

TELMISARTAN

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AT

DECREASE PROTEINURIA

Treatment

prospective, randomized, blind

AT

DECREASE PROTEINURIA

BENAZEPRIL vs. TELMISARTAN, initial findings

Treatment

◦ 112 vs. 112 cats ◦ Creatinine: not different (IRIS Stage 2) ◦ Urea: not different ◦ UPC: not different ◦ Urine specific gravity: not different ◦ Blood pressure: not different

AT

DECREASE PROTEINURIA

UPC

Treatment

BENAZEPRIL vs. TELMISARTAN, follow-up 6 months

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Treatment

AT

DECREASE PROTEINURIA

UPC

AT

DECREASE PROTEINURIA

BENAZEPRIL vs. TELMISARTAN, other

Treatment

◦ Blood pressure (vs. T=0): not different ◦ Hematocrit (vs. T=0): not different ◦ Side effects: not different

AT

DECREASE PROTEINURIA

BENAZEPRIL vs. TELMISARTAN, other

Treatment

◦ Blood pressure (vs. T=0): not different ◦ Hematocrit (vs. T=0): not different ◦ Side effects: not different

◦ Survival???

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Treatment

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UPC  0.4

ACEi



DECREASE PROTEINURIA

29 GN dogs, enalapril vs. placebo, for 6 months

Treatment

◦ UPC:  vs.  ◦ Blood pressure:  vs. = ◦ Creatinine: = ◦ Albumin: =

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DECREASE PROTEINURIA

ACEi



26 CKD dogs, benazepril (+/-eparina) vs. placebo, for 6

Treatment

months ◦ UPC:  vs. = ◦ Creatinine: = ◦ GFR:  vs. =

DECREASE PROTEINURIA

Treatment

AT



If UPC >0.5



ACEi (benazepril, enalapril) ◦ Angiotensin receptor antagonist (AT)

Treatment

◦ Aldosterone receptor antagonist 

Omega 3 (ω-6/ω-3, 5/1)



Protein restriction



Anti-platelet aggregation (aspirine, clopidogrel)



Anti-hypertension (>160/100 mm Hg)

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Trattamento

ELSE???

CORRECT DEHYDRATION ...also subcutaneous administration

Treatment



ERYTHROPOIETIN



When???

PCV < 22% or clinical signs



Human recombinant (= feline 83%) ◦ 2-3 injections/week SIDE EFFECTS

Treatment

Vomiting/nausea Hypertension Seizures Skin allergic reactions PRCA (25-30%)

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DARBOPOETIN

  

Human recombinant (+ carbohydrates) Effect in 56% 1 injection/week SIDE EFFECTS Vomiting (36%) Hypertension (41%)

Treatment

Seizures (16%) PRCA (8%)

Treatment

Feline ERYTHROPOIETIN Am J Vet Res. 2004 Oct;65(10):1355-66. Expression, bioactivity, and clinical assessment of recombinant feline erythropoietin Randolph JE, Scarlett JM, Stokol T, Saunders KM, MacLeod JN ANIMALS: 26 cats (group 1, 19 cats with anemia attributed to chronic kidney disease [CKD]; group 2, 7 cats with CKD and recombinant human erythropoietin [rhEPO]-induced red cell aplasia [RCA]). RESULTS: Biological activity of rfEPO was broadly equivalent to rhEPO in preclinical murine bioassays. Median Hct and absolute reticulocyte count in cats increased significantly during the first 3 weeks of rfEPO treatment, and median Hct generally could be maintained within a target range of 30% to 40% with periodic adjustments of rfEPO doses. Unexpectedly, 5 cats in group 1 and 3 cats in group 2 that initially responded to rfEPO treatment again developed anemia that was refractory to additional rfEPO treatments, even at higher doses. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with rfEPO can reestablish active erythropoiesis in most cats with CKD, even those with anemia attributable to rhEPO-induced RCA. Unfortunately, development of RCA during treatment with CHO cell-derived recombinant erythropoietin proteins was not eliminated as a serious safety concern, even for this feline-specific preparation.

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Treatment

Feline ERYTHROPOIETIN Am J Vet Res. 2004 Oct;65(10):1355-66. Expression, bioactivity, and clinical assessment of recombinant feline erythropoietin Randolph JE, Scarlett JM, Stokol T, Saunders KM, MacLeod JN ANIMALS: 26 cats (group 1, 19 cats with anemia attributed to chronic kidney disease [CKD]; group 2, 7 cats with CKD and recombinant human erythropoietin [rhEPO]-induced red cell aplasia [RCA]). RESULTS: Biological activity of rfEPO was broadly equivalent to rhEPO in preclinical murine bioassays. Median Hct and absolute reticulocyte count in cats increased significantly during the first 3 weeks of rfEPO treatment, and median Hct generally could be maintained within a target range of 30% to 40% with periodic adjustments of rfEPO doses. Unexpectedly, 5 cats in group 1 and 3 cats in group 2 that initially responded to rfEPO treatment again developed anemia that was refractory to additional rfEPO treatments, even at higher doses. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with rfEPO can reestablish active erythropoiesis in most cats with CKD, even those with anemia attributable to rhEPO-induced RCA. Unfortunately, development of RCA during treatment with CHO cell-derived recombinant erythropoietin proteins was not eliminated as a serious safety concern, even for this feline-specific preparation.

ERYTHROPOIETIN



When???

PCV < 22% or clinical signs



Human recombinant (= canine 81%)

Treatment

◦ PRCA 25-30% ◦ darbopoetin? 

Canine recombinant ◦ Hypertension, no PRCA

J Vet Intern Med. 2004;18:81-91. Clinical efficacy and safety of recombinant canine erythropoietin in dogs with anemia of chronic renal failure and dogs with recombinant human erythropoietininduced red cell aplasia. Randolph JE, Scarlett J, Stokol T, Macleod JN.

Treatment

ERYTHROPOIETIN

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Salvador Dalì, 1948

Eric Zini

Contact

Istituto Veterinario di Novara, Novara (Italy) ) +39 0321 46001 * [email protected]

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