Clinical Approach and Lab evaluation

Question 1

What is the GFR?

What are the primary determinants of GFR?

Answer 1

• The glomerular filtration rate is a measure of the overall function of the collective of glomeruli.
• The measure is an estimate of how much blood is passing through the glomeruli over a defined unit of time
• Total number of glomeruli
• Glomeruli structure - permeability of the glomeurli basement membrane
• Local resistance / pressure: afferent and efferent arteriolar tone
• Effective circulating volume / cardiac output

Question 2

How might the patient history differ with AKI and CKD?

Answer 2

Acute Kidney Injury:

• AKI may present suddenly with signs consistent with an acute illness (signs for a few days)
• The historical findings with AKI are typically non-specific but may include recent ingestion of a known toxin
• Know other chronic conditions that may predispose to AKI should also be considered

Chronic Kidney Disease:

• CKD is characterised by a prolonged history of polyuria and polydipsia, usually of 2-3 plus months
• Mild or moderate weight loss may be present with CKD together with a variable appetite, especially in cats
• Signs attributable to hypertension may also be present

Question 3

What laboratory variables can be similar and what laboratory variables are likely to differ with AKI versus CKD?

Answer 3

Similar:

• BUN, creatinine and SDMA should be elevated in both AKI and CKD. The severity of elevation simply relates to the severity of the underlying disease +/- concurrent hydration status
• USG is expected to be reduced in both
  
  • May be normal with post-renal causes of AKI
  • May be increased with pre-renal causes of AKI

Variable:

• Non-regenerative anaemia, often moderate is common with CKD
  
  • Anaemia can also be present in AKI - haemorrhage or haemolysis may contribute to the development of hypoxia induced renal injury
  • Hypoadrenocorticism and leptospirosis may also cause mild anaemia
• Hyperkalaemia
  
  • Common with AKI, and most often seen with post-renal obstruction as the cause
    
    • May be seen with CKD also, especially in dogs receiving ACEI or ARB (blockage of aldosterone production)
• Reanl casts and pyuria in the face of renal insufficiency is suggestive of pyelonephritis and AKI
  
  • Note that pyelonephritis can cause acute on chronic disease also.

Question 4

How might one use ancilliary tests to differentiate between AKI and CKD?

Describe the expected or common differences with such testing

Answer 4

• Ancilliary tests to differentiate AKI and CKD include:
  
  • Renal ultrasound
    
    • Most useful of the ancilliary tests. Renomegaly, obstruction/hydronephrosis, nodules/mass, renal lymphoma especially in cats
  • US of the parathyroid
    
    • Hypertrophy may be present with chronic renal disease secondary to chronic hyperphosphataemia
  • Assessment of the lamina dura around teeth
    
    • Bone loss with chronic disease secondary to chronic secondary hyperparathyroidism
  • Measurement of carbamylated haemoglobin
    
    • Reflects prevailing urea concentrations
  • Renal aspirate / biopsy
    
    • May identify chronic inflammatory, tubular or glomerular diseases. Can be useful for diagnosis of round cell neoplasia

Question 5

Discuss the differences between pre-renal, renal and post-renal azotaemia.

Answer 5

1. Pre-renal azotaemia is caused by a reduced GFR secondary to reduction in the effective circulating volume - dehydration or hypovolaemia.
   
   • With pre-renal azotaemia, concentrating ability is maintained and USG > 1.030 (dog), > 1.035 (cat)
2. Renal azotaemia is caused by a reduced GFR due to primary renal disease
   
   • USG should be reduced
3. Post-renal azotaemia is caused by increased resistance to filtration (reduced GFR) secondary to obstruction or due to resorption of urine and waste products into the blood stream due to urinary tract rupture.
   
   • USG can be variable and is often normal unless there is concurrent renal disease

Question 6

Describe the variations that may be seen that can make categorising azotaemia difficult

Answer 6

• Some cats with chronic renal disease maintain USG > 1.035
  
  • Concentrating ability may be maintained until there is < 1/8 renal function
• Primary glomerular disease may retain tubular function and concentrating ability even after developing azotaemia
• Many diseases causing pre-renal azotaemia may contribute to a reduced USG
  
  • liver disease - low urea - low concentrating gradient
  • Hypoadrenocorticism - reduced sodium absorption due to lack of aldosterone - reduced medullary concentration gradient
  • Diabetes insipidus
  • Diuretic use

Question 7

What measures can be used to assess GFR in dogs and cats?

Answer 7

1. Serum creatinine, once elevated, is linearly related to GFR and a good surrogate
   
   • Cannot be utilised when in a normal range
   • Once the creatinine is elevated, other measures of GFR are not indicated
2. Renal clearance of solutes
   
   • Inulin - considered the gold standared
   • Exogenous creatinine
   • Iohexol
     
     • Requires collection of 12-24 hours of urine
     • Difficult methodology
3. Plasma clearance
   
   • Inulin (not recommended), exogenous creatinine, iohexol and radio-labelled markers
   • Single sample methods - 180 minutes after iohexol in cats

Question 8

How is urea formed and in what conditions can urea be altered from normal?

Answer 8

• Urea is formed within the liver (and kidney) from the metabolism of ammonia (within the urea cycle)
• Urea is essentially an end product of protein catabolism that can be freely dissolved in and passively excreted within the urine

Decreased urea:

• Decreased formation - hepatic disease especially PSVA
• Decreased protein intake

Increased urea:

• Reduced excretion due to renal disease
• Increased concentration due to dehydration (increased tubular resorption with reduced urine production rates)
• Increased protein intake
• Gastrointesintal bleeding
• Increased protein catabolism:
  
  • Burns
  • Fever / infection
  • Starvation
  • Hyperthyroidism

Question 9

What is creatinine and how is it formed?

What conditions can alter the blood levels of creatinine?

Answer 9

• Creatinine is a breakdown product of the conversion of creatine to creatine phosphate, an important reaction in muscle metabolism.
• Creatine phosphate (phosphocreatine) serves as a source of high-energy phosphates used to replenish ATP stores especially in the muscle, heart and brain
• Creatinine is produced at a fairly constant rate provided muscle mass remains stable

Increased creatinine:

• Reduced GFR
  
  • Pre-renal or renal causes
• Increased muscle mass
• Recent ingestion of a protein meal

Decreased creatinine:

• Reduced muscle mass
• Overhydration

Question 10

Whatis SDMA and how does it relate to renal function?

Answer 10

• SDMA is symmetric dimethylarginine
• SDMA is produced by intranuclear methylation of L-arginine residues in all nucleated cells
• SDMA production is continuous and not dependent on muscle mass
• SDMA is excreted primarily via the kidneys with some evidence of uptake in the liver
• SDMA is not secreted in the renal tubules
• Therefore an increased SDMA may be a useful early marker of reduced renal clearance or GFR

Question 11

How can urine protein be assessed?

Note the potential confounding factors with each test

Answer 11

• Urine dipstick - colorimetric biochemical reagent
  
  • Lower limit of detection is ~ 30 mg/dL
  • Sensitivity of 80%
  • Poor specificity in cats
  • False negatives with Bence-Jones proteinuria, dilute or acidic urine
  • Alkaline or highly concentrated feline urine can lead to false positives
• Sulfosalicylic Acid Test
  
  • Can be used to detect protein at a lower threshold of ~ 5 mg/dL
  • Can detect Bence-Jones proteinuria
• Microalbuminuria
  
  • Major limitiation is the high sensitivity and low specificity of the test
• Urine protein creatinine ratio
  
  • Most commonly used method to quantify urinary protein
  • Considerable day-to-day individual variablilty occurs
    
    • up to 80% with a UP:Cr of ~ 0.5
    • up to 35% with a UP:Cr of ~ 12

Question 12

When might acquisition of a renal biopsy be useful?

When kidney disease is present, in what circumstances would a renal biopsy be unnecessary

Answer 12

• Renal biopsy is primarily indicated when there is suspicion of primary glomerular disease
• Biopsy is indicated if there is persistent proteinuria despite anti-proteinuric therapy or a progressive increase in proteinuria despite standard therapy
• Biopsy is also indicated for suspected neoplasia
  
  • FNA can be sufficient for a diagnosis of lymphoma in 78% of dogs.
• Biopsy is rarely helpful in cases of AKI, as the specific inciting cause is unlikely to be identified and management unlikely to be altered
• Biopsy is not indicated for tubulointerstitial disease or with advanced CKD - again therapy is directed at support, not the inciting cause
• Biopsy is not indicated if there is a strong index or suspicion for amyloidosis or a hereditary nephropathy
• Care with coagulopathy

Question 13

Briefly note the required sample size/type for a renal biopsy

List the specific assessments that should be performed on all renal biopsies.

Answer 13

• 2-3 core cut needle biopsy specimens of >1 cm is typically sufficient
• An 18G needle will be sufficient in most patients, however there is increased numbers of glomeruli and reduced crush artifact with 16G or 14G needles.

Samples should be assessed with

1. Light microscopy - formalin fixed tissue
   
   • H & E
   • Masson’s trichome - assessed for collagen/connective tissue
   • Periodic-Acid Schiff identifies junction between tissue compartments
   • Jones methenamine silver - assess the basement membrane (immune deposits)
   • Congo red - amyloid
2. Transmission electromicroscopy - glutaraldehyde fixed
   
   • Sensitive for the identifcation of immune complexes
3. Immunofluorescence
   
   • Can be used to identify the origins of immune complexes - IgG, IgM, IgA, C1q. C3, lambda, kappa light chains