The “Ins and Outs” of

Chronic Kidney Disease in Dogs

Sabrina Clark, DVM, DACVP, PhDHeska CorporationAugust 19, 2021

Overview• Review • Diagnosis• Management Considerations• Monitoring• Future Directions• Questions

The Kidney

https://fineartamerica.com/featured/1-kidney-and-nephron-illustration-monica-schroeder.html

The Glomerulus

The glomerular filtration barrier

Ichimura K, et al., Scientific Reports, 2015

Renal Function• Glomerular filtration rate (GFR)– Most useful and sensitive test

1. Plasma iohexol clearance2. Plasma creatinine clearance

• Why use creatinine (CREA) as an indirect measurement?– Produced at a constant rate in vivo– Freely filtered by glomeruli– Minimally resorbed/secreted by tubules

[CREA]blood correlates with renal excretion

CREA

Chronic Kidney Disease (CKD)

End Stage Renal

Disease (ESRD)

Renal Fibrosis and CKD• Interstitial fibrosis is a characteristic finding– Correlates with decline of renal function

Masson’s Trichrome staining for collagen

International Renal Interest Society

www.iris-kidney.com

CKD in Dogs• Most common kidney disease• A leading cause of morbidity and

mortality• Severe disease at time of diagnosis• There is NO cure

– Focus on disease management

Causes of CKD

• Complex disease influenced by a combination of genetic, individual, and environmental factors

• Various “triggers” or risk factors– Familial Kidney Disease– Acquired Kidney Disease

• Glomerular disease**• Comorbid conditions

– Periodontal disease*• Chronic medication• Chronic infection

– Aging

Clues in the Clinical Signs• Polyuria/polydipsia

– Reported up to 6 months prior to diagnosis1

• Weight loss– Reported up to 4 months prior1

• Periodontal disease– Reported up to 1-year prior1

• Vomiting, lethargy, refusing to eat > 1 day1

1Bartlett, et al. Vet Med Int. 2010

Diagnosis of CKD• Glomerular filtration rate (GFR)• Renal biopsy• More commonly used:– Blood

• Blood urea nitrogen (BUN)• Serum creatinine (sCr)• Symmetric dimethylarginine (SDMA)

– Urine• Urine specific gravity (USG)• Urine protein:urine creatinine ratio (UPC)• Glucosuria (normoglycemic)

– Imaging

Limitations• Dehydration• BUN

– Influenced by:• Diet• Liver disease• Urinary flow rate

– GI bleeding• sCr

– Increased in heavily muscled dogs– Decreased in animals with muscle loss/cachexia– High individuality– Large variation in reference intervals– Compensatory hypertrophy of nephrons in early disease

The Diagnostic Challenge

i.e., FIBROSIS

sCr may remain within the reference interval or increase

slightly

Increase in sCr

Confirm Renal Azotemia• Differentiate:

– Pre-renal– Renal– Post-renal

• Any treatment that may influence concentrating ability?• Disorders that cause pre-renal azotemia with concomitant decreased USG

– Hypoadrenocorticism– Diabetes/DKA– Pyometra– HyperCa– Liver disease

***A urinalysis should ALWAYS be a part of the

minimum database.***

Keeping up with the CREA

• Monitor trends• Small but significant– Individual variation is minimal–

investigated• Keep it constant– Analytical variations

• Use in conjunction with SDMA to evaluate renal function

CREATININE

Symmetric dimethylarginine(SDMA)

• A methylated amino acid (arginine)– Produced in the nucleus of all cells– Eliminated by glomerular filtration

• Advantages over sCr– More sensitive to changes in GFR– Less influenced by extra-renal factors– Better suited for use in population-based reference intervals

• Must be interpreted in conjunction with hydration status

IRIS Staging

International Renal Interest Societywww.iris-kidney.com

IRIS Stage 1 CKD

• One or more of the following:– Either CREA or SDMA increasing within

the reference interval – Persistent increased in SDMA (>14 μg/dL)– Abnormal kidney imaging– Persistent renal proteinuria (UPC >0.5)

When to Biopsy• Renal Pathology

– Glomerular Disease• Persistent proteinuria

– Renomegaly (particularly a mass)– History of familial renal disease

• If results will alter treatment considerations• If results will alter prognosis• Monitoring response to treatment and determine

progression

https://vet.osu.edu/vmc/international-veterinary-renal-pathology-service-ivrps

CKD Management

• Goals:1. Control clinical signs of uremia2. Minimize disturbances

associated with fluid, electrolyte and acid-base balanceSupport adequate nutrition

4. Modify progression of CKD to prolong survival time and improve quality **Plan should be tailored to

individual needs**

CKD Management• Unlimited access to fresh water• Nutritional management is crucial– Proper diet can encompass:

• Benefits from reduced protein intake• Decrease phosphorous intake• Control Na/Cl consumption• Increased omega-• Increase antioxidants (Vitamins C and E)

– Considered at Stage 1 and when CREA >2.0 mg/dL

• Control proteinuria• Control hypertension

Monitoring• Depends on Stage of CKD

– Non-azotemia: every 6 months– Azotemia: every 2-– Uremia: every 2-4 weeks

• Any evidence of malnutrition• Should include:

– CBC (PCV/TS), Chemistry profile and UA– UPC– Blood pressure– +/- urine culture and imaging

• Trends in UPC– Decreased UPC with increased azotemia may reflect

glomerulosclerosis and obsolesence

FUTURE DIRECTIONS

microRNAs• microRNAs (miR)– Small non-coding RNAs– Important in biological

functions– Post-transcriptional gene

regulators– Highly conserved– Aberrant expression in

pathologic processes

Protein

miRNAs in Circulation miRNAs as Biomarkers

NormalAffected

miR-21

• miR-21– A crucial regulatory RNA– Vital role in fibrosis– Renal fibrosis correlates with decline of renal function

miR-21 Expression During Disease Progression

Mild azotemia

Marked azotemia(ESRD)

*= p-

Renal miR-21 Expression Correlates with Kidney Function

sCr (mg/dL)

r=0.7975

UPC

GFR (mL/min/kg)

r=-

In situ hybridization: miR-21

MS1 MS5

Unaf

fect

ed

MS1 MS5

Affe

cted

400X 400X 400X

Urinary Expression: miR-21

*= p-

*

Unaffected Affected

T1 T2T2 T1

Urinary Expression: miR-X

*

*= p-

*

Unaffected AffectedT1 T2 T1 T2

*

Urinary Expression: miR-Y

*

**

*= p-

*

Unaffected AffectedT1 T1T2 T2

Future Directions• Advance the understanding of molecular mechanisms of

disease development• Compliment traditional diagnostics tools

– Use as a supplemental tool in critically ill patients– Evaluate prognostic considerations– Improve approach to management– Monitor progression and response to treatment

• Production of potential therapeutic targets

CKD Key Points• Early detection is crucial

– You can diagnosis CKD without azotemia

• Pay attention to owner observations• Monitor trends in the individual patient• Main goal in management is improving quality and

quantity of life– Nutritional therapy is imperative– Not a “one size fits all” approachpp

Grant ID# D14CA-904

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