Chronic renal failure Stephen P. DiBartola, DVM Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus,

Chronic renal failureChronic renal failure

Stephen P. DiBartola, DVMStephen P. DiBartola, DVM

Department of Veterinary Clinical SciencesDepartment of Veterinary Clinical Sciences

College of Veterinary MedicineCollege of Veterinary Medicine

Ohio State UniversityOhio State University

Columbus, OH 43210Columbus, OH 43210

The Nephronauts

Chronic renal failure (CRF)Chronic renal failure (CRF)Chronic renal failure (CRF)Chronic renal failure (CRF)

• Occurs when compensatory mechanisms Occurs when compensatory mechanisms of the diseased kidneys are no longer able of the diseased kidneys are no longer able to maintain the EXCRETORY, to maintain the EXCRETORY, REGULATORY, and ENDOCRINE REGULATORY, and ENDOCRINE functions of the kidneysfunctions of the kidneys

• Resultant retention of nitrogenous Resultant retention of nitrogenous solutes, derangements of fluid, electrolyte solutes, derangements of fluid, electrolyte and acid-base balance, and failure of and acid-base balance, and failure of hormone production constitute CRFhormone production constitute CRF

Causes of CRF in dogsCauses of CRF in dogsCauses of CRF in dogsCauses of CRF in dogs

• Chronic tubulointerstitial nephritis of unknown causeChronic tubulointerstitial nephritis of unknown cause• Chronic pyelonephritisChronic pyelonephritis• Chronic glomerulonephritisChronic glomerulonephritis• AmyloidosisAmyloidosis• Familial renal diseasesFamilial renal diseases• Hypercalcemic nephropathyHypercalcemic nephropathy• Chronic obstruction (hydronephrosis)Chronic obstruction (hydronephrosis)• Sequel to acute renal disease (e.g., leptospirosis)Sequel to acute renal disease (e.g., leptospirosis)

CRF may affect 0.5 to 1.0% of the geriatric canine populationCRF may affect 0.5 to 1.0% of the geriatric canine population

Causes of CRF in catsCauses of CRF in catsCauses of CRF in catsCauses of CRF in cats• Chronic tubulointerstitial nephritis of unknown causeChronic tubulointerstitial nephritis of unknown cause• Chronic pyelonephritisChronic pyelonephritis• Chronic glomerulonephritisChronic glomerulonephritis• Amyloidosis (familial in Abyssinians)Amyloidosis (familial in Abyssinians)• Polycystic kidney disease (familial in Persians)Polycystic kidney disease (familial in Persians)• Chronic obstruction (hydronephrosis)Chronic obstruction (hydronephrosis)• Sequel to acute renal diseaseSequel to acute renal disease• Neoplasia (e.g. renal lymphoma)Neoplasia (e.g. renal lymphoma)• Granulomatous interstitial nephritis due to FIPGranulomatous interstitial nephritis due to FIP

CRF may affect 1.0 to 3.0% of the geriatric feline populationCRF may affect 1.0 to 3.0% of the geriatric feline population

Causes of CRF in large animalsCauses of CRF in large animalsCauses of CRF in large animalsCauses of CRF in large animals

• HorseHorse• Chronic Chronic

glomerulonephritisglomerulonephritis• Chronic interstitial Chronic interstitial

nephritis of nephritis of unknown causeunknown cause

• Chronic Chronic pyelonephritispyelonephritis

• AmyloidosisAmyloidosis

• CowCow• Chronic pyelonephritisChronic pyelonephritis• Chronic interstitital Chronic interstitital

nephritis of unknown nephritis of unknown causecause

• AmyloidosisAmyloidosis• Renal infarction due to Renal infarction due to

sepsissepsis• Renal vein thrombosisRenal vein thrombosis• LeptospirosisLeptospirosis• Renal lymphomaRenal lymphoma

Differentiation of CRF from ARFDifferentiation of CRF from ARFDifferentiation of CRF from ARFDifferentiation of CRF from ARF

• Renal sizeRenal size• History of previous PU/PDHistory of previous PU/PD• Non-regenerative anemiaNon-regenerative anemia• Weight loss and poor haircoatWeight loss and poor haircoat• Parathyroid gland size on ultrasoundParathyroid gland size on ultrasound• Carbamylated hemoglobinCarbamylated hemoglobin• HypothermiaHypothermia• HyperkalemiaHyperkalemia

Uremia as an intoxicationUremia as an intoxicationUremia as an intoxicationUremia as an intoxication

• No single compound likely to explain No single compound likely to explain the diversity of uremic symptomsthe diversity of uremic symptoms

• Urea, guanidine compounds, Urea, guanidine compounds, polyamines, aliphatic amines, polyamines, aliphatic amines, indoles, myoinositol, trace elements, indoles, myoinositol, trace elements, “middle molecules”“middle molecules”

• PTH is the best characterized uremic PTH is the best characterized uremic toxintoxin

Concept of hyperfiltrationConcept of hyperfiltrationConcept of hyperfiltrationConcept of hyperfiltration

• Total GFR = Total GFR = SNGFRSNGFR

• In progressive renal In progressive renal disease, decline in disease, decline in total GFR is offset total GFR is offset by increased by increased SNGFR in remnant SNGFR in remnant nephronsnephrons


• After an acute reduction After an acute reduction in renal mass, total GFR in renal mass, total GFR increases 40-60% over a increases 40-60% over a period of several monthsperiod of several months

• Example: GFR falls from Example: GFR falls from 40 to 20 ml/min after 40 to 20 ml/min after uninephrectomy but 2 uninephrectomy but 2 months later is 30 ml/minmonths later is 30 ml/min


• SNGFR = KSNGFR = Kff(P(PGCGC-P-PTT--GCGC))• Increase in SNGFR occurs Increase in SNGFR occurs

due to alterations in due to alterations in determinants of GFR: Kdeterminants of GFR: Kff and Pand PGCGC

• These changes helpful in These changes helpful in the short term but the short term but maladaptive in the long runmaladaptive in the long run

Better check Better check notes on GFR notes on GFR and RBF!and RBF!

Proteinuria and glomerular sclerosis in Proteinuria and glomerular sclerosis in remnant nephrons are adverse effects of remnant nephrons are adverse effects of hyperfiltration that may lead to progression of hyperfiltration that may lead to progression of renal diseaserenal disease

Proteinuria and glomerular sclerosis in Proteinuria and glomerular sclerosis in remnant nephrons are adverse effects of remnant nephrons are adverse effects of hyperfiltration that may lead to progression of hyperfiltration that may lead to progression of renal diseaserenal disease


• In RATS, dietary protein restriction In RATS, dietary protein restriction reduces hyperfiltration and abrogates the reduces hyperfiltration and abrogates the maladaptive responsemaladaptive response

• In DOGS, this may NOT be trueIn DOGS, this may NOT be true• 17% protein diet failed to prevent 17% protein diet failed to prevent

hyperfiltration in dogs with 94% renal hyperfiltration in dogs with 94% renal ablation (Brown 1991)ablation (Brown 1991)• 8% protein diet caused malnutrition and 8% protein diet caused malnutrition and

increased mortality in dogs with 92% renal increased mortality in dogs with 92% renal ablation (Polzin 1982)ablation (Polzin 1982)

Factors contributing to the progressive Factors contributing to the progressive nature of renal diseasenature of renal disease

Factors contributing to the progressive Factors contributing to the progressive nature of renal diseasenature of renal disease

• Species differences and extent of reduction in Species differences and extent of reduction in renal massrenal mass

• Functional and morphologic changes in Functional and morphologic changes in remnant kidneyremnant kidney

• Time followedTime followed

• Dietary factorsDietary factors

• Systemic complications of renal insufficiencySystemic complications of renal insufficiency

• Therapeutic interventionsTherapeutic interventions

Progession of renal disease: Species Progession of renal disease: Species differencres and extent of reduction in differencres and extent of reduction in renal massrenal mass

Progession of renal disease: Species Progession of renal disease: Species differencres and extent of reduction in differencres and extent of reduction in renal massrenal mass• Experimental rats: 75-80% reduction in renal Experimental rats: 75-80% reduction in renal

mass results in progressionmass results in progression• DogsDogs• Clinical cases: YesClinical cases: Yes• Experimental: 85-95% reduction in renal massExperimental: 85-95% reduction in renal mass

• CatsCats• Clinical cases: YesClinical cases: Yes• Experimental: Cats with 83% reduction in renal Experimental: Cats with 83% reduction in renal

mass did not progress over 12 monthsmass did not progress over 12 months

Progression of renal disease: Functional Progression of renal disease: Functional and morphologic changes in remnant and morphologic changes in remnant renal tissuerenal tissue

Progression of renal disease: Functional Progression of renal disease: Functional and morphologic changes in remnant and morphologic changes in remnant renal tissuerenal tissue

• Hyperfiltration increases movement of Hyperfiltration increases movement of proteins across glomerular capillaries into proteins across glomerular capillaries into Bowman’s space and mesangiumBowman’s space and mesangium

• Increased protein traffic is toxic to the Increased protein traffic is toxic to the kidneykidney

• End result may be glomerular sclerosis End result may be glomerular sclerosis and tubulointerstitial nephritisand tubulointerstitial nephritis

Progression of renal disease: Progression of renal disease: Time followedTime followedProgression of renal disease: Progression of renal disease: Time followedTime followed

• Dogs with 75% renal mass reduction fed 19, 27 Dogs with 75% renal mass reduction fed 19, 27 and 56% protein (1% Pi) and followed 4 years and 56% protein (1% Pi) and followed 4 years did NOT show evidence of progressiondid NOT show evidence of progression

• 3/10 dogs with 88% renal mass reduction fed 3/10 dogs with 88% renal mass reduction fed 26% protein (0.9% Pi) progressed over 21-24 26% protein (0.9% Pi) progressed over 21-24 monthsmonths

• 10/12 dogs with 94% renal mass reduction fed 10/12 dogs with 94% renal mass reduction fed 17% protein (1.5% Pi) progressed over 24 17% protein (1.5% Pi) progressed over 24 monthsmonths

Progression of renal disease: DietProgression of renal disease: DietProgression of renal disease: DietProgression of renal disease: Diet

• ProteinProtein

• PhosphorusPhosphorus

• CaloriesCalories

• LipidsLipids

Diet and progression of renal Diet and progression of renal disease: Protein restrictiondisease: Protein restrictionDiet and progression of renal Diet and progression of renal disease: Protein restrictiondisease: Protein restriction

• Role of low protein diet in slowing Role of low protein diet in slowing progression of renal disease is progression of renal disease is controversialcontroversial

• Prevention of hyperfiltration by low Prevention of hyperfiltration by low protein diet may not be feasible in dogs protein diet may not be feasible in dogs without inducing malnutritionwithout inducing malnutrition

• Low protein diets may have other Low protein diets may have other beneficial effects (limitation of beneficial effects (limitation of proteinuria)proteinuria)

Diet and progression of renal Diet and progression of renal disease: Phosphorus restrictiondisease: Phosphorus restrictionDiet and progression of renal Diet and progression of renal disease: Phosphorus restrictiondisease: Phosphorus restriction

• Slows progression of renal Slows progression of renal diseasedisease

• Prevents or reverses renal Prevents or reverses renal secondary hyperparathyroidismsecondary hyperparathyroidism

• Limits renal interstitial Limits renal interstitial mineralization, inflammation and mineralization, inflammation and fibrosisfibrosis

Diet and progression of renal Diet and progression of renal disease: Caloric restrictiondisease: Caloric restrictionDiet and progression of renal Diet and progression of renal disease: Caloric restrictiondisease: Caloric restriction

• Extremely low protein diets are Extremely low protein diets are unpalatable and experimental rats unpalatable and experimental rats with remnant kidney consumed less with remnant kidney consumed less foodfood

• One study showed improvement in One study showed improvement in proteinuria and renal morphologic proteinuria and renal morphologic changes when calories (but not changes when calories (but not protein) were restrictedprotein) were restricted

Diet and progression of renal Diet and progression of renal disease: Lipidsdisease: LipidsDiet and progression of renal Diet and progression of renal disease: Lipidsdisease: Lipids

-6 PUFA may hasten progression of -6 PUFA may hasten progression of renal disease whereas renal disease whereas -3 PUFA are -3 PUFA are renoprotectiverenoprotective

-3 PUFA promote production of -3 PUFA promote production of “good” prostaglandins and limit “good” prostaglandins and limit production of “bad” prostaglandinsproduction of “bad” prostaglandins

Beneficial effects of Beneficial effects of -3 PUFA in -3 PUFA in renal diseaserenal diseaseBeneficial effects of Beneficial effects of -3 PUFA in -3 PUFA in renal diseaserenal disease

• Decreased cholesterol and Decreased cholesterol and triglyceridestriglycerides

• Decreased urinary eicosinoid Decreased urinary eicosinoid excretionexcretion

• Decreased proteinuriaDecreased proteinuria• Preservation of GFRPreservation of GFR• Less severe renal morphologic Less severe renal morphologic

changeschanges

Progression of renal disease: Progression of renal disease: Systemic complications of renal Systemic complications of renal insufficiencyinsufficiency

Progression of renal disease: Progression of renal disease: Systemic complications of renal Systemic complications of renal insufficiencyinsufficiency

• Systemic hypertensionSystemic hypertension

• Urinary tract infectionUrinary tract infection

• Fluid, electrolyte, and acid-base Fluid, electrolyte, and acid-base abnormalitiesabnormalities

Progression of renal disease: Progression of renal disease: Therapeutic interventionsTherapeutic interventionsProgression of renal disease: Progression of renal disease: Therapeutic interventionsTherapeutic interventions

• ACE inhibitors (e.g. enalapril)ACE inhibitors (e.g. enalapril)• Decrease proteinuriaDecrease proteinuria• Decrease blood pressureDecrease blood pressure• Limit glomerular sclerosisLimit glomerular sclerosis• Slow progressionSlow progression

• Low protein dietLow protein diet• Decrease proteinuriaDecrease proteinuria• Limit uremic symptomatologyLimit uremic symptomatology• May not limit hyperfiltrationMay not limit hyperfiltration

Concept of external balanceConcept of external balanceConcept of external balanceConcept of external balance

Solute input Solute input from dietfrom diet

Solute output Solute output in urinein urine

The challenge to the diseased kidneys is to maintain external The challenge to the diseased kidneys is to maintain external solute balance in the face of progressively declining GFRsolute balance in the face of progressively declining GFR

Intact nephron hypothesis (Bricker)Intact nephron hypothesis (Bricker)Intact nephron hypothesis (Bricker)Intact nephron hypothesis (Bricker)

• ““In the presence of a In the presence of a heterogeneity of morphologic heterogeneity of morphologic changes in the nephrons of changes in the nephrons of diseased kidneys, there is a diseased kidneys, there is a relative homogeneity of relative homogeneity of glomerulotubular balance”glomerulotubular balance”

Maintenance of glomerulotubular Maintenance of glomerulotubular balance in progressive renal diseasebalance in progressive renal diseaseMaintenance of glomerulotubular Maintenance of glomerulotubular balance in progressive renal diseasebalance in progressive renal disease

• For any given solute, the diseased For any given solute, the diseased kidneys maintain GT balance as GFR kidneys maintain GT balance as GFR declines by:declines by:• DECREASING the FRACTION of the DECREASING the FRACTION of the

filtered load of that solute that is filtered load of that solute that is REABSORBED andREABSORBED and• INCREASING the FRACTION of the INCREASING the FRACTION of the

filtered load of that solute that is filtered load of that solute that is EXCRETEDEXCRETED

““Trade off” hypothesis (Bricker)Trade off” hypothesis (Bricker)““Trade off” hypothesis (Bricker)Trade off” hypothesis (Bricker)

• ““The biological price to be paid for The biological price to be paid for maintaining external solute maintaining external solute balance for a given solute as renal balance for a given solute as renal disease progresses is the disease progresses is the induction of one or more induction of one or more abnormalities of the uremic state”abnormalities of the uremic state”

““Trade off” hypothesisTrade off” hypothesis““Trade off” hypothesisTrade off” hypothesis

• Renal secondary hyperparathyroidism Renal secondary hyperparathyroidism (maintenance of normal calcium and (maintenance of normal calcium and phosphorus balance at the expense of bone phosphorus balance at the expense of bone mineral) is the most well-characterized mineral) is the most well-characterized example of the “trade off” hypothesisexample of the “trade off” hypothesis

• This “mal”-adaptive process can be This “mal”-adaptive process can be prevented by PROPORTIONAL REDUCTION prevented by PROPORTIONAL REDUCTION in the intake of phosphorusin the intake of phosphorus

Different responses for Different responses for different solutesdifferent solutes

Different responses for Different responses for different solutesdifferent solutes

• No regulation (A)No regulation (A)

• Complete Complete regulation (C)regulation (C)

• Limited Limited regulation (B)regulation (B)

Different responses for different solutesDifferent responses for different solutesDifferent responses for different solutesDifferent responses for different solutes

• NO REGULATIONNO REGULATION Solutes handled by GFR Solutes handled by GFR alone (e.g. urea, creatinine)alone (e.g. urea, creatinine)• Plasma concentration reflects GFRPlasma concentration reflects GFR

• COMPLETE REGULATIONCOMPLETE REGULATION Some solutes Some solutes handled by GFR and a combination of tubular handled by GFR and a combination of tubular reabsorption and secretion (e.g. Nareabsorption and secretion (e.g. Na++, K, K++))• Normal plasma concentration maintained until Normal plasma concentration maintained until

GFR < 5% of normalGFR < 5% of normal• LIMITED REGULATIONLIMITED REGULATION Some solutes handled Some solutes handled

by GFR and a combination of tubular by GFR and a combination of tubular reabsorption and secretion (e.g. Pi, Hreabsorption and secretion (e.g. Pi, H++))• Normal plasma concentration maintained until Normal plasma concentration maintained until

GFR < 15-20% of normalGFR < 15-20% of normal

BUN, creatinine (no regulation)BUN, creatinine (no regulation)BUN, creatinine (no regulation)BUN, creatinine (no regulation)

• Azotemia does Azotemia does not develop not develop until 75% or until 75% or more of the more of the nephron nephron population has population has become non-become non-functionalfunctional

Water balance (complete regulation)Water balance (complete regulation)Water balance (complete regulation)Water balance (complete regulation)

• Ability to produce concentrated urine Ability to produce concentrated urine and to excrete a water load both are and to excrete a water load both are impaired in CRFimpaired in CRF

• Clinical manifestations: PU/PDClinical manifestations: PU/PD

• Increased solute load per residual Increased solute load per residual functioning nephron (osmotic diuresis) functioning nephron (osmotic diuresis) is the MOST important factor is the MOST important factor contributing to the concentrating defectcontributing to the concentrating defect

Impaired concentrating abilityImpaired concentrating abilityImpaired concentrating abilityImpaired concentrating ability

• Develops when 67% of nephron Develops when 67% of nephron population becomes non-functionalpopulation becomes non-functional

• Corresponds to USG 1.007-1.015 or Corresponds to USG 1.007-1.015 or UUOsmOsm 300-600 mOsm/kg 300-600 mOsm/kg

• Some cats retain considerable Some cats retain considerable concentrating ability even after concentrating ability even after development of azotemiadevelopment of azotemia

Why does polyuria develop?Why does polyuria develop?Why does polyuria develop?Why does polyuria develop?

• Consider a 10 kg dog producing 333 Consider a 10 kg dog producing 333 ml urine per day with average Uml urine per day with average UOsmOsm of of 1,500 mOsm/kg (i.e. solute load of 1,500 mOsm/kg (i.e. solute load of 500 mOsm/day)500 mOsm/day)

• With CRF, this dog might have a fixed With CRF, this dog might have a fixed UUOsmOsm of 500 mOsm/kg and would of 500 mOsm/kg and would require a urine volume of 1,000 ml to require a urine volume of 1,000 ml to excrete the same 500 mOsm of soluteexcrete the same 500 mOsm of solute

NormalNormal DiseasedDiseased

Number of nephronsNumber of nephrons 1,000,0001,000,000 250,000250,000

Total GFR (ml/min)Total GFR (ml/min) 4040 1515

SNGFR (nl/min)SNGFR (nl/min) 4040 6060

Urine output (ml/day)Urine output (ml/day) 333333 1,0001,000

Urine output (ml/min)Urine output (ml/min) 0.230.23 0.690.69

Urine output per nephron (nl/min)Urine output per nephron (nl/min) 0.230.23 2.762.76

% Filtered water reabsorbed% Filtered water reabsorbed 99.499.4 95.495.4

% Filtered water excreted% Filtered water excreted 0.60.6 4.64.6

If GFR is decreased, how can polyuria develop?If GFR is decreased, how can polyuria develop?

NaNa++ balance in CRF: Complete regulation balance in CRF: Complete regulationNaNa++ balance in CRF: Complete regulation balance in CRF: Complete regulation

• As GFR declines, fractional reabsorption of As GFR declines, fractional reabsorption of NaNa++ decreases (fractional excretion decreases (fractional excretion increases)increases)

• Natriuretic substances probably play a role Natriuretic substances probably play a role (e.g. ANP)(e.g. ANP)

• Less flexibility in NaLess flexibility in Na++ handling handling• Ability to excrete an acute NaAbility to excrete an acute Na++ load impaired load impaired• Ability to conserve NaAbility to conserve Na++ impaired impaired

• Changes in NaChanges in Na++ intake should be made intake should be made gradually in CRF patientsgradually in CRF patients

KK++ balance in CRF: Complete regulation balance in CRF: Complete regulationKK++ balance in CRF: Complete regulation balance in CRF: Complete regulation

• As GFR declines, fractional reabsorption of As GFR declines, fractional reabsorption of KK++ decreases (fractional excretion decreases (fractional excretion increases)increases)

• Aldosterone contributes but is not essentialAldosterone contributes but is not essential• Less flexibility in KLess flexibility in K++ handling handling• Reduced ability to tolerate a KReduced ability to tolerate a K++ load load

• May have reduced ability to conserve KMay have reduced ability to conserve K++ (hypokalemia occurs in 10-30% of dogs and (hypokalemia occurs in 10-30% of dogs and cats with CRF)cats with CRF)

CaCa+2+2 balance in CRF: Complete regulation balance in CRF: Complete regulationCaCa+2+2 balance in CRF: Complete regulation balance in CRF: Complete regulation

Normal calcium balance depends on Normal calcium balance depends on interactions of PTH, calcitriol, and calcitonin interactions of PTH, calcitriol, and calcitonin acting on kidney, gut, and boneacting on kidney, gut, and bone

CaCa+2+2 balance in CRF: Complete regulation balance in CRF: Complete regulationCaCa+2+2 balance in CRF: Complete regulation balance in CRF: Complete regulation

• Kidney is normal Kidney is normal site of conversion site of conversion of 25-OH of 25-OH cholecalciferol to cholecalciferol to 1,25-(OH)1,25-(OH)22 cholecalciferol cholecalciferol (calcitriol) by 1(calcitriol) by 1 hydroxylasehydroxylase

CaCa+2+2 balance in CRF balance in CRFCaCa+2+2 balance in CRF balance in CRF

• Total serum CaTotal serum Ca+2+2 concentration concentration usually is normal but ionized usually is normal but ionized hypocalcemia occurs in 40% of CRF hypocalcemia occurs in 40% of CRF dogsdogs• ““Mass Law” effect due to increased PiMass Law” effect due to increased Pi• Decreased production of calcitriol by Decreased production of calcitriol by

kidneys due to hyperphosphatemia kidneys due to hyperphosphatemia and/or parenchymal renal diseaseand/or parenchymal renal disease• Impaired gut absorption of calciumImpaired gut absorption of calcium

CaCa+2+2 balance in CRF balance in CRFCaCa+2+2 balance in CRF balance in CRF

• Hypercalcemia occurs in 5-10% of dogs Hypercalcemia occurs in 5-10% of dogs with CRFwith CRF

• Ionized CaIonized Ca+2+2 may be normal or low may be normal or low

• May be difficult to determine which came May be difficult to determine which came first: renal failure or hypercalcemiafirst: renal failure or hypercalcemia

• Hypercalcemia (and hypophosphatemia) Hypercalcemia (and hypophosphatemia) develops in some horses with CRFdevelops in some horses with CRF

Phosphorus balance in CRF: Phosphorus balance in CRF: Limited regulationLimited regulationPhosphorus balance in CRF: Phosphorus balance in CRF: Limited regulationLimited regulation

• CaCa+2+2 and Pi balance maintained by and Pi balance maintained by progressive increase in PTH (renal progressive increase in PTH (renal secondary hyperparathyroidism)secondary hyperparathyroidism)

• Leads to bone demineralization and Leads to bone demineralization and possibly other toxic effects (“Trade possibly other toxic effects (“Trade off” hypothesis)off” hypothesis)

Phosphorus balance in CRF: Limited Phosphorus balance in CRF: Limited regulationregulationPhosphorus balance in CRF: Limited Phosphorus balance in CRF: Limited regulationregulation

• Hyperparathyroidism is a consistent Hyperparathyroidism is a consistent finding in progressive renal diseasefinding in progressive renal disease

• PTH decreases the TPTH decreases the TMaxMax for Pi reabsorption for Pi reabsorption

• Compensation is maximal when GFR Compensation is maximal when GFR decreases to 15-20% of normal. After this decreases to 15-20% of normal. After this point, Pi balance can only be maintained point, Pi balance can only be maintained by development of hyperphosphatemiaby development of hyperphosphatemia

Renal secondary hyperparathyroidismRenal secondary hyperparathyroidismClassical theoryClassical theory

Renal secondary hyperparathyroidismRenal secondary hyperparathyroidismClassical theoryClassical theory

• Decreased GFR causes Decreased GFR causes Pi Pi

• Mass Law effect results Mass Law effect results in in Ca Ca+2+2

CaCa+2+2 stimulates PTH stimulates PTH secretionsecretion

• Increased PTH causes Increased PTH causes increased renal increased renal excretion of Pi and excretion of Pi and mobilization of Camobilization of Ca+2+2 from bonefrom bone

Renal secondary hyperparathyroidismRenal secondary hyperparathyroidismRenal secondary hyperparathyroidismRenal secondary hyperparathyroidism

Renal secondary hyperparathyroidismRenal secondary hyperparathyroidism

Renal secondary hyperparathyroidismRenal secondary hyperparathyroidism

Renal secondary Renal secondary hyperparathyroidism hyperparathyroidism can be prevented or can be prevented or reversed by a reversed by a proportional reduction proportional reduction in phosphorus intakein phosphorus intake

Renal secondary hyperparathyroidism Renal secondary hyperparathyroidism Alternative hypothesis: Role of calcitriolAlternative hypothesis: Role of calcitriolRenal secondary hyperparathyroidism Renal secondary hyperparathyroidism Alternative hypothesis: Role of calcitriolAlternative hypothesis: Role of calcitriol

• Phosphate retention inhibits 1Phosphate retention inhibits 1 hydroxylase hydroxylase and reduces renal production of calcitrioland reduces renal production of calcitriol

• Ionized hypocalcemia due to decreased GI Ionized hypocalcemia due to decreased GI absorption of Caabsorption of Ca+2+2 stimulates PTH synthesis stimulates PTH synthesis

• Decreased numbers of calcitriol receptors in Decreased numbers of calcitriol receptors in parathyroid glands (less negative feedback)parathyroid glands (less negative feedback)

• Decreased DNA binding of calcitriol-VDR Decreased DNA binding of calcitriol-VDR complex in parathyroid glands (less negative complex in parathyroid glands (less negative feedback)feedback)

Renal secondary hyperparathyroidismRenal secondary hyperparathyroidismRenal secondary hyperparathyroidismRenal secondary hyperparathyroidism

• ““Early” in course of progressive Early” in course of progressive renal disease, phosphate restriction renal disease, phosphate restriction reduces inhibition of 1reduces inhibition of 1 hydroxylase hydroxylase and increases calcitriol synthesisand increases calcitriol synthesis

• ““Late” in course of progressive renal Late” in course of progressive renal disease, insufficient functional renal disease, insufficient functional renal mass prevents production of mass prevents production of adequate amounts of calcitriol and adequate amounts of calcitriol and replacement therapy is necessaryreplacement therapy is necessary

Renal secondary hyperparathyroidism: Renal secondary hyperparathyroidism: Phosphorus restrictionPhosphorus restrictionRenal secondary hyperparathyroidism: Renal secondary hyperparathyroidism: Phosphorus restrictionPhosphorus restriction

• Blunts or reverses renal secondary Blunts or reverses renal secondary hyperparathyroidismhyperparathyroidism• Slows progression of renal diseaseSlows progression of renal disease• Improves renal function (some Improves renal function (some

species)species)• Minimizes renal interstitial Minimizes renal interstitial

mineralization, inflammation and mineralization, inflammation and fibrosisfibrosis

Acid-base regulation: Limited Acid-base regulation: Limited regulationregulationAcid-base regulation: Limited Acid-base regulation: Limited regulationregulation

• Limitation of renal NHLimitation of renal NH44++ production is main production is main

cause of metabolic acidosis in CRFcause of metabolic acidosis in CRF

• Total NHTotal NH44++ excretion decreases in progressive excretion decreases in progressive

renal disease but NHrenal disease but NH44++ excretion per remnant excretion per remnant

nephron increases 3 to 5 foldnephron increases 3 to 5 fold

• This adaptation is maximal when GFR This adaptation is maximal when GFR decreases to 10-20% of normal and acid-base decreases to 10-20% of normal and acid-base balance then must be maintained by reduction balance then must be maintained by reduction in serum HCOin serum HCO33

--

Acid-base regulation: Limited Acid-base regulation: Limited regulationregulationAcid-base regulation: Limited Acid-base regulation: Limited regulationregulation

• Metabolic acidosis of CRF usually Metabolic acidosis of CRF usually mild due to large reservoir of buffer mild due to large reservoir of buffer (bone CaCO(bone CaCO33))

• Normochloremic (high anion gap) Normochloremic (high anion gap) acidosis “late” in course of acidosis “late” in course of progressive renal disease due to progressive renal disease due to accumulation of “unmeasured” POaccumulation of “unmeasured” PO44 and SOand SO44 anions anions

Anemia of CRFAnemia of CRFAnemia of CRFAnemia of CRF

• Non-regenerative (normochromic, Non-regenerative (normochromic, normocytic)normocytic)

• Variable in magnitude and correlated Variable in magnitude and correlated with severity of CRF (as estimated by with severity of CRF (as estimated by serum creatinine)serum creatinine)

• Serum EPO concentrations are low to Serum EPO concentrations are low to normal (inappropriate for PCV) normal (inappropriate for PCV)

Anemia of CRF: Contributory Anemia of CRF: Contributory factorsfactorsAnemia of CRF: Contributory Anemia of CRF: Contributory factorsfactors

• Main cause is inadequate production of EPO Main cause is inadequate production of EPO by diseased kidneysby diseased kidneys

• Uremic toxins reduce lifespan of circulating Uremic toxins reduce lifespan of circulating RBC and may impair erythropoiesis RBC and may impair erythropoiesis

• Platelet dysfunction promotes ongoing blood Platelet dysfunction promotes ongoing blood loss (e.g. GI tract)loss (e.g. GI tract)

• Increased RBC 2,3-DPGA decreases Hb Increased RBC 2,3-DPGA decreases Hb affinity for Oaffinity for O22 and enhances O and enhances O22 deliver to deliver to tissues (compensatory effect)tissues (compensatory effect)

Hemostasis in CRFHemostasis in CRFHemostasis in CRFHemostasis in CRF

• Abnormal platelet function (e.g. Abnormal platelet function (e.g. aggregation) but numbers normalaggregation) but numbers normal

• GI blood loss most commonGI blood loss most common• Best to check buccal mucosal Best to check buccal mucosal

bleeding time to assess risk of bleeding time to assess risk of hemorrhagehemorrhage

• Guanidines and PTH suspected to Guanidines and PTH suspected to contribute to platelet dysfunctioncontribute to platelet dysfunction

Gastrointestinal disturbances in CRFGastrointestinal disturbances in CRFOral lesionsOral lesionsGastrointestinal disturbances in CRFGastrointestinal disturbances in CRFOral lesionsOral lesions

• Foul odorFoul odor• StomatitisStomatitis• Erosions and Erosions and

ulcersulcers• Tongue tip Tongue tip

necrosis (fibrinoid necrosis (fibrinoid necrosis and focal necrosis and focal ischemia)ischemia)

Gastrointestinal disturbances in CRFGastrointestinal disturbances in CRFGastric lesionsGastric lesionsGastrointestinal disturbances in CRFGastrointestinal disturbances in CRFGastric lesionsGastric lesions

• Back diffusion of acidBack diffusion of acid• Bleeding due to Bleeding due to

platelet dysfunctionplatelet dysfunction• Bacterial NHBacterial NH44

++ production from ureaproduction from urea

• Ischemia due to Ischemia due to vascular lesionsvascular lesions

• Increased gastrinIncreased gastrin

Metabolic complications of CRFMetabolic complications of CRFMetabolic complications of CRFMetabolic complications of CRF

• Hyperglycemia due to peripheral insulin Hyperglycemia due to peripheral insulin resistanceresistance

• Catabolic effect of increased glucagonCatabolic effect of increased glucagon• Increased gastric acid due to excess gastrinIncreased gastric acid due to excess gastrin• Altered metabolism of thyroid hormones Altered metabolism of thyroid hormones

(“euthyroid sick syndrome”)(“euthyroid sick syndrome”)• Increased mineralocorticoids may contribute to Increased mineralocorticoids may contribute to

hypertensionhypertension• Impaired erythropoietin and calictriol Impaired erythropoietin and calictriol

productionproduction

Less commonly recognized Less commonly recognized disturbances in CRFdisturbances in CRFLess commonly recognized Less commonly recognized disturbances in CRFdisturbances in CRF

• Defective cell-mediated immunityDefective cell-mediated immunity• Uremic encephalopathy (related Uremic encephalopathy (related

more to rate of onset than severity more to rate of onset than severity of uremia)of uremia)• Uremic neuropathyUremic neuropathy• Uremic pneumonitisUremic pneumonitis

Hypertension in CRFHypertension in CRFHypertension in CRFHypertension in CRF

• Prevalence Prevalence uncertainuncertain• Up to 67% of dogs Up to 67% of dogs

and cats with CRFand cats with CRF

• Up to 80% of dogs Up to 80% of dogs with glomerular with glomerular diseasedisease

Hypertension in CRF Hypertension in CRF MechanismsMechanismsHypertension in CRF Hypertension in CRF MechanismsMechanisms

• Renal ischemia with activation of the Renal ischemia with activation of the renin-angiotensin systemrenin-angiotensin system

• Sympathetic nervous system stimulationSympathetic nervous system stimulation• Impaired NaImpaired Na++ excretion and ECFV excretion and ECFV

expansion when GFR very low (< 5% of expansion when GFR very low (< 5% of normal)normal)

• Primary intrarenal mechanism for NaPrimary intrarenal mechanism for Na++ retention in glomerular diseaseretention in glomerular disease

Hypertension in CRFHypertension in CRFClinical ManifestationsClinical ManifestationsHypertension in CRFHypertension in CRFClinical ManifestationsClinical Manifestations

• OcularOcular• BlindnessBlindness• Retinal detachmentRetinal detachment• Retinal hemorrhagesRetinal hemorrhages• Retinal vascular toruosityRetinal vascular toruosity

• CardiovascularCardiovascular• LV enlargementLV enlargement• Medial hypertrophy of Medial hypertrophy of

arteriesarteries• Murmurs and gallopsMurmurs and gallops

Clinical history in CRFClinical history in CRFFindings are non-specificFindings are non-specificClinical history in CRFClinical history in CRFFindings are non-specificFindings are non-specific

• Polyuria and polydipsiaPolyuria and polydipsia

• Vomiting (dogs)Vomiting (dogs)

• AnorexiaAnorexia

• Weight lossWeight loss

• LethargyLethargy

Physical findings in CRFPhysical findings in CRFPhysical findings in CRFPhysical findings in CRF• Weight lossWeight loss• Poor haircoatPoor haircoat• Oral lesions (most common in dogs)Oral lesions (most common in dogs)• Pallor of mucous membranesPallor of mucous membranes• DehydrationDehydration• Osteodystrophy (young growing dog Osteodystrophy (young growing dog

with familial renal disease)with familial renal disease)• Ascites or edema (consider glomerular Ascites or edema (consider glomerular

disease)disease)

Laboratory findings in CRFLaboratory findings in CRFLaboratory findings in CRFLaboratory findings in CRF

• Nonregenerative anemia, lymphopeniaNonregenerative anemia, lymphopenia• Isosthenuria (67% loss of nephrons)Isosthenuria (67% loss of nephrons)• Azotemia (75% loss of nephrons)Azotemia (75% loss of nephrons)• Hyperphosphatemia (85% loss of Hyperphosphatemia (85% loss of

nephrons)nephrons)

• Decreased serum HCODecreased serum HCO33--

• Variable serum CaVariable serum Ca+2+2

• Mild hyperglycemiaMild hyperglycemia

Laboratory findings in CRF: Laboratory findings in CRF: UrinalysisUrinalysisLaboratory findings in CRF: Laboratory findings in CRF: UrinalysisUrinalysis

• Isosthenuria (cats may retain Isosthenuria (cats may retain considerable concentrating ability)considerable concentrating ability)

• Persistent proteinuria with inactive Persistent proteinuria with inactive sediment, hypoalbuminemia, and sediment, hypoalbuminemia, and hypercholesterolemia suggest hypercholesterolemia suggest glomerular diseaseglomerular disease

• Pyuria and bacteriuria suggest UTI Pyuria and bacteriuria suggest UTI but do not localize itbut do not localize it

Management of CRF: General Management of CRF: General principlesprinciplesManagement of CRF: General Management of CRF: General principlesprinciples

• Search for reversible Search for reversible causes (e.g. causes (e.g. pyelonephritis, pyelonephritis, obstruction, obstruction, hypercalcemia)hypercalcemia)

• Don’t pass judgement Don’t pass judgement on animal until on animal until several days of several days of conscientious fluid conscientious fluid therapytherapy

Isn’t that bandage a little tight?

Conservative medical management of CRFConservative medical management of CRFConservative medical management of CRFConservative medical management of CRF

• Free access to water at all times!Free access to water at all times!• Protein and caloriesProtein and calories• Sodium chlorideSodium chloride• Alkali and potassium and replacementAlkali and potassium and replacement• Phosphorus restrictionPhosphorus restriction• H2 receptor blockersH2 receptor blockers• Hormone replacement (erythropoietin, calcitriol)Hormone replacement (erythropoietin, calcitriol)• Anabolic steroidsAnabolic steroids• Blood pressure controlBlood pressure control• Avoid stress (SQ fluids at home by the owner)Avoid stress (SQ fluids at home by the owner)

Conservative medical management Conservative medical management of CRF: Protein restriction?of CRF: Protein restriction?Conservative medical management Conservative medical management of CRF: Protein restriction?of CRF: Protein restriction?

• Relieve uremic Relieve uremic symptomatology symptomatology and improve and improve patient well-beingpatient well-being

• Can hyperfiltration Can hyperfiltration be reduced?be reduced?

Conservative medical management Conservative medical management of CRF: Protein restrictionof CRF: Protein restrictionConservative medical management Conservative medical management of CRF: Protein restrictionof CRF: Protein restriction

• Introduce when patient has persistent mild to Introduce when patient has persistent mild to moderate azotemia in the hydrated statemoderate azotemia in the hydrated state

• Feeding moderately protein-restricted diets is Feeding moderately protein-restricted diets is preferable to extremely high or low protein preferable to extremely high or low protein dietsdiets

• Dogs require Dogs require minimumminimum of 5% of calories from of 5% of calories from proteinprotein

• Cats require Cats require minimumminimum of 20% of calories from of 20% of calories from proteinprotein

Commercial diets for CRF Commercial diets for CRF management (dry matter basis)management (dry matter basis)Commercial diets for CRF Commercial diets for CRF management (dry matter basis)management (dry matter basis)

0.2-0.3%0.2-0.3%0.2-0.3%0.2-0.3%SodiumSodium

0.5-0.6%0.5-0.6%0.2-0.3%0.2-0.3%PhosphorusPhosphorus

25-28%25-28%15-17%15-17%ProteinProtein

CatCatDogDog

Conservative medical management of Conservative medical management of CRF: Monitoring patient responseCRF: Monitoring patient responseConservative medical management of Conservative medical management of CRF: Monitoring patient responseCRF: Monitoring patient response

• Stable body weightStable body weight• Stable serum albumin Stable serum albumin

concentrationconcentration• Decreased BUN concentrationDecreased BUN concentration• Stable serum creatinine Stable serum creatinine

concentrationconcentration

Conservative medical management Conservative medical management of CRF: Non-protein caloriesof CRF: Non-protein caloriesConservative medical management Conservative medical management of CRF: Non-protein caloriesof CRF: Non-protein calories

• Adequate non-protein calories to Adequate non-protein calories to maintain body condition should maintain body condition should be provided by carbohydrate and be provided by carbohydrate and fatfat

-3 PUFA may be renoprotective -3 PUFA may be renoprotective whereas whereas -6 PUFA may hasten -6 PUFA may hasten progression of renal diseaseprogression of renal disease

Conservative medical management Conservative medical management of CRF: Sodium chlorideof CRF: Sodium chlorideConservative medical management Conservative medical management of CRF: Sodium chlorideof CRF: Sodium chloride

• Reasons for sodium restrictionReasons for sodium restriction• Documented hypertensionDocumented hypertension

• Glomerular disease (primary intrarenal Glomerular disease (primary intrarenal mechanism for sodium retention)mechanism for sodium retention)

• Make changes slowly (CRF patients Make changes slowly (CRF patients are less flexible in adjusting to are less flexible in adjusting to changes in dietary sodium)changes in dietary sodium)

Conservative medical management of Conservative medical management of CRF: Alkali and potassium replacementCRF: Alkali and potassium replacementConservative medical management of Conservative medical management of CRF: Alkali and potassium replacementCRF: Alkali and potassium replacement

• Severe metabolic acidosis (serum Severe metabolic acidosis (serum HCOHCO33

-- < 12 mEq/L) can be treated < 12 mEq/L) can be treated with NaHCOwith NaHCO33, K, K++ gluconate or K gluconate or K++ citratecitrate

• Hypokalemia may occur in 10-30% Hypokalemia may occur in 10-30% of dogs and cats with CRF and may of dogs and cats with CRF and may be treated with Kbe treated with K++ gluconate or K gluconate or K++ citratecitrate

Conservative medical management Conservative medical management of CRF: Phosphorus restrictionof CRF: Phosphorus restrictionConservative medical management Conservative medical management of CRF: Phosphorus restrictionof CRF: Phosphorus restriction

• Reversal or blunting of renal Reversal or blunting of renal secondary hyperparathyroidismsecondary hyperparathyroidism

• Prevention of soft tissue Prevention of soft tissue mineralization (including kidneys)mineralization (including kidneys)

• Improvement in renal Improvement in renal tubulointerstitial lesionstubulointerstitial lesions

• Improvement in renal function (rats)Improvement in renal function (rats)

Conservative medical management Conservative medical management of CRF: Phosphorus restrictionof CRF: Phosphorus restrictionConservative medical management Conservative medical management of CRF: Phosphorus restrictionof CRF: Phosphorus restriction

• Modified-protein diets for dogs and Modified-protein diets for dogs and cats with CRF also are low in cats with CRF also are low in phosphorusphosphorus

• Initially try dietary phosphorus Initially try dietary phosphorus restriction alonerestriction alone

• If inadequate, add phosphorus If inadequate, add phosphorus bindersbinders

Conservative medical management of Conservative medical management of CRF: Phosphorus restrictionCRF: Phosphorus restrictionConservative medical management of Conservative medical management of CRF: Phosphorus restrictionCRF: Phosphorus restriction

• Ideally, monitor renal secondary Ideally, monitor renal secondary hyperparathyroidism by serial hyperparathyroidism by serial measurement of serum PTHmeasurement of serum PTH

• Evaluate serum phosphorus Evaluate serum phosphorus concentration after 12 hour fastconcentration after 12 hour fast

• Aim for serum phosphorus Aim for serum phosphorus concentration of 2.5 to 5.0 mg/dL concentration of 2.5 to 5.0 mg/dL

Conservative medical management Conservative medical management of CRF: Phosphorus bindersof CRF: Phosphorus bindersConservative medical management Conservative medical management of CRF: Phosphorus bindersof CRF: Phosphorus binders

• Most phosphorus binders contain Most phosphorus binders contain CaCa+2+2 or Al or Al+3+3

• Constipation is common side effectConstipation is common side effect• AlAl+3+3 containing phosphorus binders containing phosphorus binders

are not considered safe in humans are not considered safe in humans with CRF due to Alwith CRF due to Al+3+3 retention retention

• Risk of AlRisk of Al+3+3 intoxication in dogs and intoxication in dogs and cats is uncertaincats is uncertain

Conservative medical management of Conservative medical management of CRF: Phosphorus bindersCRF: Phosphorus bindersConservative medical management of Conservative medical management of CRF: Phosphorus bindersCRF: Phosphorus binders

• Aluminum hydroxideAluminum hydroxide• Aluminum carbonateAluminum carbonate• Calcium acetateCalcium acetate• Calcium carbonateCalcium carbonate

90 mg/kg/day divided and 90 mg/kg/day divided and given with within 2 hours given with within 2 hours of feedingof feeding

Slightly lower dosage of calcium acetate may be necessary due Slightly lower dosage of calcium acetate may be necessary due to more efficient phosphate bindingto more efficient phosphate binding


• Aluminum hydroxideAluminum hydroxide• Effective phosphorus Effective phosphorus

binderbinder• Risk of aluminum Risk of aluminum

intoxication?intoxication?• Becoming difficult to Becoming difficult to

find in storesfind in stores


• Calcium carbonateCalcium carbonate• Effective phosphorus Effective phosphorus

binderbinder• Also provides Also provides

calciumcalcium• Monitor carefully in Monitor carefully in

patients receiving patients receiving calcitriol due to risk calcitriol due to risk of hypercalcemiaof hypercalcemia

Conservative medical management Conservative medical management of CRF: Phosphorus bindersof CRF: Phosphorus bindersConservative medical management Conservative medical management of CRF: Phosphorus bindersof CRF: Phosphorus binders

• Sevelamer HCl (RenagelSevelamer HCl (Renagel))• Does not contain CaDoes not contain Ca+2+2 or Al or Al+3+3

• 30-60 mg/kg/day divided and given with 30-60 mg/kg/day divided and given with foodfood• May cause GI adverse effects including May cause GI adverse effects including

constipationconstipation• At extremely high dosage may interfere At extremely high dosage may interfere

with GI absorption of folic acid, vitamin with GI absorption of folic acid, vitamin D, and vitamin KD, and vitamin K• ExpensiveExpensive

Medical Management of CRF: Medical Management of CRF: Uremic GastroenteritisUremic GastroenteritisMedical Management of CRF: Medical Management of CRF: Uremic GastroenteritisUremic Gastroenteritis

• Plasma gastrin concentrations are Plasma gastrin concentrations are high in dogs and cats with CRFhigh in dogs and cats with CRF

• Degree of hypergastrinemia Degree of hypergastrinemia correlates with severity of CRFcorrelates with severity of CRF

• Potential clinical manifestationsPotential clinical manifestations• AnorexiaAnorexia• VomitingVomiting• Gastrointestinal bleedingGastrointestinal bleeding

Medical Management of CRF: Medical Management of CRF: H2 Receptor BlockersH2 Receptor BlockersMedical Management of CRF: Medical Management of CRF: H2 Receptor BlockersH2 Receptor Blockers

• Decrease gastric Decrease gastric acid secretionacid secretion• CimetidineCimetidine (5 mg/kg q12h)(5 mg/kg q12h)• RanitidineRanitidine (2 mg/kg q12h)(2 mg/kg q12h)• FamotidineFamotidine (1 mg/kg q24h)(1 mg/kg q24h)

Medical Management of CRF: Medical Management of CRF: H2 Receptor BlockersH2 Receptor BlockersMedical Management of CRF: Medical Management of CRF: H2 Receptor BlockersH2 Receptor Blockers

• FamotidineFamotidine• Once per day Once per day

dosingdosing• 1 mg/kg1 mg/kg

Medical Management of CRF: Medical Management of CRF: Endocrine replacement therapyEndocrine replacement therapyMedical Management of CRF: Medical Management of CRF: Endocrine replacement therapyEndocrine replacement therapy

• ErythropoietinErythropoietin

• CalcitriolCalcitriol

Medical Management of CRFMedical Management of CRFHormonal Replacement: ErythropoietinHormonal Replacement: ErythropoietinMedical Management of CRFMedical Management of CRFHormonal Replacement: ErythropoietinHormonal Replacement: Erythropoietin

• Effects in treated Effects in treated dogs and catsdogs and cats• Resolution of anemiaResolution of anemia• Weight gainWeight gain• Improved appetiteImproved appetite• Improved haircoatImproved haircoat• Increased alertnessIncreased alertness• Increased activityIncreased activity

Not approved for use in dogs and cats!Not approved for use in dogs and cats!


• Consider in symptomatic Consider in symptomatic dogs and cats with PCV dogs and cats with PCV < 20%< 20%

• Starting dosage 100 U/kg Starting dosage 100 U/kg SQ 3X per weekSQ 3X per week

• Supplement with FeSOSupplement with FeSO44

• When PCV > 30% When PCV > 30% decrease to 2X per weekdecrease to 2X per week


• Monitor iron status with serum iron and Monitor iron status with serum iron and TIBCTIBC

• Monitor PCV weekly using same Monitor PCV weekly using same technique (table top centrifuge or Coulter technique (table top centrifuge or Coulter counter) every timecounter) every time

• Target PCV range: 30 to 40%Target PCV range: 30 to 40%

• Depending on severity of anemia may take Depending on severity of anemia may take 3 to 4 weeks for PCV to enter target range3 to 4 weeks for PCV to enter target range

Medical Management of CRFMedical Management of CRFErythropoietin: Adverse EffectsErythropoietin: Adverse EffectsMedical Management of CRFMedical Management of CRFErythropoietin: Adverse EffectsErythropoietin: Adverse Effects

• Antibody formationAntibody formation• VomitingVomiting• SeizuresSeizures• HypertensionHypertension• UveitisUveitis• Hypersensitivity-like mucocutaneous Hypersensitivity-like mucocutaneous

reactionreaction

Medical Management of CRFMedical Management of CRFErythropoietin: Adverse EffectsErythropoietin: Adverse EffectsMedical Management of CRFMedical Management of CRFErythropoietin: Adverse EffectsErythropoietin: Adverse Effects

• High risk of antibody formationHigh risk of antibody formation

• Occurs 30 to 160 days after starting treatmentOccurs 30 to 160 days after starting treatment

• Progressive decrease in PCV and marked Progressive decrease in PCV and marked increase in bone marrow M:E ratio while increase in bone marrow M:E ratio while receiving EPOreceiving EPO

• Discontinue EPO if antibody formation Discontinue EPO if antibody formation suspectedsuspected

• Prolonged transfusion dependence may resultProlonged transfusion dependence may result

Medical Management of CRFMedical Management of CRFErythropoietin: The futureErythropoietin: The futureMedical Management of CRFMedical Management of CRFErythropoietin: The futureErythropoietin: The future

• Recombinant canine and feline Recombinant canine and feline erythropoietin (Cornell erythropoietin (Cornell University)University)

• Erythropoietin gene therapy in Erythropoietin gene therapy in cats (University of Florida, Ohio cats (University of Florida, Ohio State University)State University)

Medical Management of CRFMedical Management of CRFHormonal Replacement: CalcitriolHormonal Replacement: CalcitriolMedical Management of CRFMedical Management of CRFHormonal Replacement: CalcitriolHormonal Replacement: Calcitriol

• Enhances Enhances gastrointestinal gastrointestinal absorption of calcium absorption of calcium and corrects ionized and corrects ionized hypocalcemiahypocalcemia

• Reduces PTH Reduces PTH secretion by secretion by occupying calcitriol occupying calcitriol receptors on receptors on parathyroid glandsparathyroid glands


• Used only after Used only after hyperphosphatemia hyperphosphatemia controlledcontrolled

(Ca (Ca Pi < 60-70) Pi < 60-70)• Watch for hypercalcemia Watch for hypercalcemia

(especially with Ca(especially with Ca+2+2 containing Pi binders)containing Pi binders)

• Rapidly lowers serum Rapidly lowers serum PTH concentrationPTH concentration


• Extremely low Extremely low dosage required: dosage required: 2.5 to 3.5 2.5 to 3.5 ng/kg/dayng/kg/day

• Requires Requires reformulation by reformulation by compounding compounding pharmacypharmacy

http://www.islandpharmacy.com/http://www.islandpharmacy.com/


• Monitoring patients on calcitriolMonitoring patients on calcitriol• Clinical appearance may be Clinical appearance may be

unreliableunreliable

• Follow serum PTH concentrationFollow serum PTH concentration

• Long-term benefit to animal Long-term benefit to animal unknownunknown

Medical Management of CRF:Medical Management of CRF:Anabolic steroidsAnabolic steroidsMedical Management of CRF:Medical Management of CRF:Anabolic steroidsAnabolic steroids

• Equivocal effectiveness in dogs with Equivocal effectiveness in dogs with CRFCRF

• Several productsSeveral products• MethyltestosteroneMethyltestosterone• StanozololStanozolol• OxymetholoneOxymetholone• Nandrolone decanoateNandrolone decanoate

• Cats may develop hepatotoxicity after Cats may develop hepatotoxicity after stanozolol administrationstanozolol administration• AnorexiaAnorexia• Increased ALT and ALPIncreased ALT and ALP• HyperbilirubinemiaHyperbilirubinemia• Vitamin K-responsive coagulopathyVitamin K-responsive coagulopathy• Centrilobular hepatic lipidosis and cholestasis on Centrilobular hepatic lipidosis and cholestasis on

liver biopsyliver biopsy

Medical Management of CRF:Medical Management of CRF:Anabolic steroidsAnabolic steroidsMedical Management of CRF:Medical Management of CRF:Anabolic steroidsAnabolic steroids

Medical Management of CRF:Medical Management of CRF:Blood Pressure AssessmentBlood Pressure AssessmentMedical Management of CRF:Medical Management of CRF:Blood Pressure AssessmentBlood Pressure Assessment

• Oscillometric or Doppler Oscillometric or Doppler methodology acceptable in dogsmethodology acceptable in dogs

• Doppler methodology more Doppler methodology more reliable in catsreliable in cats

Medical Management of CRF Medical Management of CRF Hypertension: “White Coat Artifact”Hypertension: “White Coat Artifact”Medical Management of CRF Medical Management of CRF Hypertension: “White Coat Artifact”Hypertension: “White Coat Artifact”

• Makes it difficult to decide if a cat is truly Makes it difficult to decide if a cat is truly hypertensivehypertensive

• Mean 24-hr systolic blood pressure by Mean 24-hr systolic blood pressure by radiotelemetry:radiotelemetry:• Normal cats: 126 mm HgNormal cats: 126 mm Hg• CRF cats: 148 mm HgCRF cats: 148 mm Hg

• During clinical examination:During clinical examination:• Normal cats: 143 mm HgNormal cats: 143 mm Hg• CRF cats: 170 mm HgCRF cats: 170 mm Hg

Belew et al. J Vet Int Med 13:134, 1999Belew et al. J Vet Int Med 13:134, 1999

Medical Management of CRF:Medical Management of CRF:Blood Pressure AssessmentBlood Pressure AssessmentMedical Management of CRF:Medical Management of CRF:Blood Pressure AssessmentBlood Pressure Assessment

• Patient, trained technicianPatient, trained technician• Quiet, undisturbed Quiet, undisturbed

environmentenvironment• Sufficient time for Sufficient time for

acclimationacclimation• Correct cuff sizeCorrect cuff size• Several sequential Several sequential

measurementsmeasurements• Average sequential readingsAverage sequential readings

I don’t think he’s waving at you

Medical Management of CRFMedical Management of CRFHypertension: To treat or not?Hypertension: To treat or not?Medical Management of CRFMedical Management of CRFHypertension: To treat or not?Hypertension: To treat or not?

• BP consistently BP consistently > 170 mm Hg> 170 mm Hg• High BP and fundic High BP and fundic

lesionslesions• Retinal hemorrhageRetinal hemorrhage• Vascular tortuosityVascular tortuosity• Retinal edemaRetinal edema• Intra-retinal transudateIntra-retinal transudate• Retinal detachmentRetinal detachment

Medical Management of CRF:Medical Management of CRF:Treatment of HypertensionTreatment of HypertensionMedical Management of CRF:Medical Management of CRF:Treatment of HypertensionTreatment of Hypertension

• Dietary salt restrictionDietary salt restriction• Commercial pet foods designed for CRF Commercial pet foods designed for CRF

often also are sodium-restrictedoften also are sodium-restricted

• DiureticsDiuretics• Risk of dehydration and pre-renal Risk of dehydration and pre-renal

azotemia greater with loop diuretics azotemia greater with loop diuretics (e.g. furosemide) than with thiazides (e.g. furosemide) than with thiazides (e.g. hydrochlorothiazide)(e.g. hydrochlorothiazide)


• AmlodipineAmlodipine• 0.18 mg/kg in dogs 0.18 mg/kg in dogs

or 0.625 to 1.25 mg or 0.625 to 1.25 mg per cat PO q24hper cat PO q24h

• Recheck BP one Recheck BP one week after starting week after starting drugdrug


• EnalaprilEnalapril• 0.5 mg/kg q12h or 0.5 mg/kg q12h or

q24hq24h• Effect on blood Effect on blood

pressure may be pressure may be modestmodest

• May have other May have other potentially potentially beneficial effects beneficial effects on kidneyon kidney


• Other anti-hypertensive agentsOther anti-hypertensive agents• Hydralazine (arterial vasodilator)Hydralazine (arterial vasodilator)

• Prazosin (Prazosin (11 adrenergic blocker) adrenergic blocker)

• Propranolol (nonspecific Propranolol (nonspecific blocker) blocker)

Medical Management of CRF:Medical Management of CRF:Avoid stressAvoid stressMedical Management of CRF:Medical Management of CRF:Avoid stressAvoid stress

• Manage on Manage on outpatient basis outpatient basis whenever whenever possiblepossible

• Consider SQ Consider SQ fluids at home by fluids at home by ownerowner

Medical Management of CRF:Medical Management of CRF:Why is survival time so variable?Why is survival time so variable?Medical Management of CRF:Medical Management of CRF:Why is survival time so variable?Why is survival time so variable?

• Rate of progression Rate of progression varies among varies among individualsindividuals

• Different individuals are Different individuals are diagnosed at different diagnosed at different stages of diseasestages of disease

• Activity of underlying Activity of underlying disease may fluctuatedisease may fluctuate

• Treatment may affect Treatment may affect progressionprogression

Slope of 1/SCr vs time is a ROUGH Slope of 1/SCr vs time is a ROUGH indicator of progressionindicator of progression

Medical Management of CRF:Medical Management of CRF:Findings indicative of a poor prognosisFindings indicative of a poor prognosisMedical Management of CRF:Medical Management of CRF:Findings indicative of a poor prognosisFindings indicative of a poor prognosis

• Severe intractable anemiaSevere intractable anemia• Advanced osteodystrophyAdvanced osteodystrophy• Inability to maintain fluid Inability to maintain fluid

balancebalance• Progressive azotemia Progressive azotemia

despite treatmentdespite treatment• Progressive weight lossProgressive weight loss• Severe endstage renal Severe endstage renal

lesions on biopsylesions on biopsy

Documents

Chronic renal failure Stephen P. DiBartola, DVM Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus,