1
Q
What are the functions of the kidney?
A
- Clear metabolic wastes from blood
- Conserve nutrients
- Glucose
- Protein
- Maintain water, electrolyte, and A-B balance
- Hormone production
- Erythropoietin
- Vitamin D
- Renin
- Hormone degradation and/or excretion
- PTH, Growth Hormone, Secretin, Cholecystokinin, glucagon, gastrin, prolactin, insulin, thyrotropin and ADH
- Enzyme degradation and/or excretion
- amylase, lipase
2
Q
What determines what through the glomerular filtration barrier when healthy?
A
- size (mol wt > 68,000 not filtered)
- Charge
- Basement membrane - negative charge
- Negatively charged molecules may be repelled
3
Q
During health what stays in the blood and what passes through the barrier?
A
- Stays:
- Cells (WBC, RBC, Platelets)
- Most plasma proteins ( Albumin & larger proteins)
- Passes:
- Water
- Solutes
- Electrolytes
- Glucose
- Urea
- Small proteins (other)
4
Q
What are the major physiologic processes of the nephron?
A
- Glomerular filtration (passive)
- Substances move from plasma to tubules
- Tubular resorption (passive & active)
- Substances move from tubules to plasma
- Tubular secretion (passive & active)
- Substances move from plasma to tubules
- Water Regulation
5
Q
What is the Glomerular Filtration Rate (GFR)?
A
- Volume of plasma filtered from glomerular capillaries into Bowman’s space per unit of time
- Measured by determining rate of clearance of a substance from plasma
- GFR: rate substances are cleared from plasma via glomeruli
- ⇣ GFR: substances cleared slower; stay in plasma longer
6
Q
What does GFR depend on?
A
- Renal blood flow
- # of functional nephrons
- Hydrostatic pressure in Bowman’s capsule
7
Q
How can renal function be evaluated?
A
- Glomerular filtration - look for protein in urine
- Glomerular filtration rate - Look for accumulation of waste products in blood (UN, creatinine)
- Ability to concentrate urine - urine specific gravity
8
Q
What is osmolality?
A
- Total solute concentration
- Concentration of solutes per kg Water (mmol/kg H2O)
- Urine Osmolality varies greatly -
- H2O conservation
- Solutes excreted
9
Q
How can osmolality and USG be measured?
A
- Osmometer (measures osmolality)
- Freezing point assay, not convenient, more accurate
- Measure depends on the number of particles in the volume of water
- Refractometer (measures USG)
- Convenient, less accurate
- Depends on particle weight and how each particle bends light
- Prone to interference - difference between how glucose, electrolytes, urea, proteins, lipids, and other substances refract light
10
Q
How are Urine Osmolality and USG related?
A
- Typically excellent correlation between osmolality & USG
- As osmolality increases, USG increases by an approximate factor of 30
- Both change with # of particles/volume
- USG also changes with types of particle
11
Q
How does the kidney handle water?
A
- Kidneys receive ~25% of cardiac output
- ~99% of water entering the tubules is resorbed
- Healthy person (70 kg)
- ~180L of water enters the kidney
- ~1-2 L of urine excreted daily
12
Q
What is Antidiuretic hormone (ADH)?
A
- Synonym = vasopressin
- Synthesized in the hypothalamus
- Secreted from the posterior pituitary gland (neurohypophysis)
- Interacts with receptors on the cells of the distal tubules and collecting ducts
- Opens water channels via aquaporin proteins (minutes)
13
Q
What re the stimuli for ADH secretion?
A
- Plasma hyperosmolality
- Osmoreceptors (hypothalamus)
- ⇣ cardiovascular pressure (hypovolemia)
- Baroreceptors
- ⇡ angiotensin
14
Q
What is the result of ADH?
A
- Conserve body water to ⇣plasma osmolality & ⇡blood volume
15
Q
What are the major events of the nephron segments that influence osmolality?
A
- Proximal CT - removes volume
- no change in concentration
- Descending LoH - removes H2O
- ⇡ concentration
- Ascending LoH - removes solute
- dilutes (⇣⇣ concentration)
- Distal nephron - removes H2O
- ⇡ concentration
16
Q
What is needed to produce concentrated urine?
A
- Adequate number of functional nephrons
- Adequate production o ADH from pituitary
- Distal nephron epithelial cells must be responsive to ADH
- Hypertonic interstitium in the renal medulla
- Must be a concentration gradient between tubular fluid and interstitium (osmolality of the interstitium > osmolality of the tubular fluid
- Urea, Na+, Cl- = major contributors
17
Q
What are the expected USG for dehydrated animals?
A
- Dog: > 1.030
- Cat: >1.080
- Horses/Cattle: >1.50
18
Q
What are the possible clinical interpretation of USG?
A
- Urine osmolality > plasma osmolality
- USG > 1.013
- interpret with hydration status
- Urine osmolality = plasma osmolality
- Isosthenuria
- USG = 1.007 - 1.013
- in a dehydrated animal, indicates kidneys have not concentrated nor diluted the tubular fluid
- Urine osmolality < plasma osmolality
- Hyposthenuria
- USG ≤ 1.006
- Implies that the kidneys have actively diluted the tubular fluid
- NOT renal failure
19
Q
What is anuria?
A
lack of urine production
20
Q
What is Dysuria
A
painful or difficult urination
21
Q
what is oliguria
A
production of an abnormally small amount of urine
22
Q
What is pollakiuria
A
indicating increased frequency of urination
Doesn’t indicate urine volume
23
Q
what is polydipsia
A
increased water consumption
24
Q
what is polyuria
A
production of excessive amounts of urine
25
What are the routine laboratory tests to assess renal function?
* Glomerular filtration adequate (GFR)
* Urea Nitrogen
* Serum creatinine
* SDMA
* Integrity of glomerular structure
* Urine protein
* Urine protein : urine creatine ratio
* Ability to concentrate and dilute urine
* USG
* comparison of urine & plasma osmolality
* Provocative tests of urine concentrating ability
* water deprivation test
* Urinalysis
* USG, Chemistry, and sediment examination
* assesses more than the urinary tract
26
What is Azotemia?
Increased concentration of Urea Nitrogen (UN or BUN) and/or Creatinine
27
How is urea synthesized and excreted?
* Ammonium (NH4+) goes through the urea cycle in the liver to become urea
* Goes through the renal system
* ~50% is resorbed in the proximal tubule
* depends on flow rate and H2O resorption
* **⇣ GFR = ⇡UN**
* ~10% resorbed in collecting tubule
28
What causes increased urea formation?
* High protein diet (mild, transient effect)
* GI hemorrhage
* Disorders that increase endogenous protein catabolism
29
What causes decreased urea formation?
* Hepatic failure/shunt
* Malnutrition
* Diuresis
30
What are alternate routes of excretion for Urea Nitrogen?
* Saliva, sweat, GI tract
* Minimal to no effect on UN concentration in dogs & cats
* GI tract excretion of urea is significant in horses and ruminants
* UN is not a sensitive indicator of GFR in those species
* Bacteria in the rumen (cattle/sheep/goats) or cecum (horses) degrade urea to NH4+ to make amino acids
31
How does Urea Nitrogen drive recovery of water/concentration of urine in the collecting ducts
* Urea diffuses readily across most cell membranes along a concentration gradient
* Rapid equilibration among intracellular and extracellular fluid compartments (~90min)
* Equilibrium between erythrocytes, plasma/serum
* Whole blood UN = Serum UN
* Urea contributes to the renal medullary concentration gradient along with electrolytes
32
What tubes need to be used when testing for UN?
* **Serum (red top tube)**
* Plasma (green top tube)
* Stable for 1 day at room temp, several days at 4-6C, and 2-3 months frozen
33
How is creatinine Metabolized
* Creatinine is a waste product from the normal breakdown of muscle tissue
* the amount formed daily is constant for any animal
* Production proportional to muscle mass
* Removed almost exclusively via renal excretion
* Freely filtered through glomerular barrier into ultrafiltrate
* Not resorbed by tubules
* Excreted in urine
34
How is creatinine Metabolized
* Creatinine is a waste product from the normal breakdown of muscle tissue
* the amount formed daily is constant for any animal
* Production proportional to muscle mass
* Removed almost exclusively via renal excretion
* Freely filtered through glomerular barrier into ultrafiltrate
* Not resorbed by tubules
* Excreted in urine
35
Where is creatinine measured?
in serum or plasma (Green or red tube) NOT whole blood
36
What causes increased Creatinine (Ct) levels?
* Decreased GFR
* it does NOT increase with increased muscle catabolism
37
What causes decreased Creatinine?
* May not be clinically significant
* Consider:
* decreased muscle mass
* hypoproteinemia
38
What is the relationship between UN and Ct in dogs/cats?
* UN & Ct **increase in parallel** when GFR is decreased as a result of **renal failure**
* **Prerenal azotemia** can cause a disproportionately **greater increase in UN than creatinine**
* increased tubular resorption of urea (urea absorbed with water)
* **GI hemorrhage ⇢ increased UN**
* many animals with renal disease are **anorectic** or eat a **low protein diet** ⇢ **decreased UN relative to creatinine**
* Extremely **cachectic** (physical wasting) animals have **decreased muscle mass** and may have decreased creatinine compared with UN
39
What do the levels of UN/Ct indicate in horses/ruminants
Creatinine more specific for renal compromise than UN because urea is metabolized by bacteria in the rumen or cecum
40
What are the different types of Azotemia?
* ⇡ UN and/or ⇡Crt concentration in serum or plasma (or blood)
* **Prerenal**: primary cause is pre-glomerulus
* **Renal**: primary cause is nephron
* **Postrenal**: primary cause is after the nephron
41
What are possible causes of Pre-renal azotemia?
* Azotemia results from processes outside of the kidneys
* UN & Creatinine are increased
* _Urine is concentrated_
* Possible causes:
* **Decreased renal blood flow = decreased GFR**
* Dehydration
* hypovolemia / fluid maldistribution
* Severely decreased cardiac output
* **increased production of urea and/or creatinine**
* Urea
* high protein diet
* GI hemorrhage
* Creatinine
* Heavily muscled animal
42
What is Renal azotemia?
* Primary cause is within the nephron
* **Azotemia results from** any form of renal disease that causes enough damage to the kidney to **decrease the GFR**
* Loss of functional nephrons ⇢ GFR is decreased even if renal blood flow is normal
* UN and creatinine are increased
* urine is _NOT concentrated_ in the face of dehydration
* decreased concentrating ability
* Isosthenuric urine (1.007 - 1.013) indicates an **_in_**ability to concentrate and dilute
43
What is Post-renal azotemia?
* Primary problem is after the nephron
* Results from a problem that interferes with excretion of urine somewhere distal to the nephron
* UN and Crt are increased
* _Urine concentration varies_
* Ex:
* **Ureteral / urethral obstruction -** hydrostatic pressure within the Bowman's capsule is increased and GFR is decreased
* **Rupture / leakage** along the urinary outflow tract (kidney, ureter, bladder, urethra) causing leakage of urine into abdominal cavity
44
How is Azotemia different from Uremia?
* **Azotemia** - increased concentration of non-protein nitrogen compounds in blood (UN and Crt)
* **Uremia**:
* _Clinical syndrome_ associated with renal failure
* **Azotemia +** severe **physical consequences of renal failure**
* Polyuria / polydipsia
* Vomiting / diarrhea
* Ammonia odor of breath
* GI ulcers
* Nonregenerative anemia
* Weigh loss
* Convulsions
* Death
45
What _abnormal_ laboratory results are expected in azotemic animals?
* **Sodium and Chloride**
* ⇡ with Prerenal azotemia
* Low / WRI with renal failure due to decreased resorption
* **Potassium (excreted by kidney)**
* ⇡ in oliguric / anuric renal failure (ARF)
* ⇣ in cats/cows with polyuric renal failure (CRF)
* Most common electrolyte abnormality in cats with CRF - may cause marked muscle weakness
* **Phosphate**
* Excretion is ⇣ when GFR ⇣ for any reason
* _Usually_ **_⇡_** in animals with moderate to marked azotemia
* **Magnesium**
* _⇡_ with ⇣GFR
* **Calcium**
* _Dogs/cats/cattle:_
* _WRI / slightly decreased_ with renal failure
* hypercalcemia with azotemia is more likely to be the cause for renal disease than the result (but can develop secondary to renal failure)
* _Horses_ rely on renal excretion of calcium
* _High_ in most horses with renal failure
* **Hematocrit**
* WRI / ⇡ in pre-renal azotemia and ARF
* Non-regenerative anemia in CRF (decreased RBC life-span & Epo production)
* **Total Protein, Albumin**
* WRI / ⇡ in pre-renal azotemia +/- ARF
* only reason for increased albumin concentration is **dehydration**
* WRI / ⇣ in CRF (especially with glomerular proteinuria)
* **Acid/base**
46
What is SDMA?
* Symmetric Dimethylarginine (SDMA)
* Kidney excretory function biomarker
47
Why would SDMA be elevated?
* In dogs/cats with renal disease
* ⇡ [SDMA] before ⇡ [Creatinine]
* ⇡ [SDMA] before ⇡ [Urea]
* Prerenal azotemia:
* ⇡ proteolysis ⇢ ⇡⇡ production ⇢ ⇣ renal blood flow ⇢ ⇣ GFR
* Renal azotemia:
* ⇣ number of nephrons ⇢ ⇣ GFR
* Postrenal azotemia:
* Obstruction ⇣ ⇣ GFR
* Urine leakage
48
What is an indicator of Stage 1 CKD?
Persistent elevation in SDMA in a hydrated and urinating dog/cat without azotemia indicates reduced renal function
49
What are the mechanisms of Polyuria?
* **Lack of ADH production**
* Central diabetes insipidus (pathologic)
* Psychogenic polydipsia (behavioral)
* **Distal tubule / collecting duct cells cannot respond to ADH**
* Nephrogenic diabetes insipidus
* **Must be a concentration gradient between tubular fluid and interstitium** (Must have osmolality of the interstitium \> osmolality of the tubular fluid)
* Solute diuresis
* Reduced medullary interstitium osmolality
50
What is Solute diuresis?
* When water is not resorbed
* Can occur when the kidneys are functioning normally but are presented with increased solute (eg Diabetes Miletus)
* Can occur when there are decreased # of functional nephrons
* ⇡ solute load on the available nephrons
51
What is Chronic Renal disease?
* No universally accepted definition or criteria for staging
* Major Criteria -
* Evidence of GFR
* Evidence of ⇣ concentrating ability
52
What are the Stages of Chronic Renal Disease? (for this course)
* **Decreased Renal Reserve:**
* GFR ~50% normal
* Clinically healthy - NOT azotemic or polyuric
* **Chronic renal insufficiency:**
* 25-50% function
* Azotemia, anemia, ⇣concentrating ability, polyuria
* **Chronic renal failure:**
* \<20-25% function
* Azotemia, anemia, ⇣ concentrating ability, polyuria
* Electrolyte imbalance, clinical signs of uremia
* **End-stage renal disease:**
* \<5% function
* Terminal uremia signs and oliguria or anuria
Percentages Not true for cats\*
53
What is the cause of Polyuria in Chronic Renal Disease?
* Loss of functional Nephrons
* More solute presented to remaining functional nephrons
* ⇡ load through nephrons
* Solute diuresis
* Medullary hypertonicity is not maintained
* Medullary tissue damage or abnormal blood flow
* ⇣Na+, Cl- and urea reabsorption
* Damaged cells less responsive to ADH
54
What is the evidence for Renal insufficiency/Failure?
* Azotemia
* Inappropriaely low USG (1.007 - 1.013)
* Inability to concentrate or dilute
55
What is the evidence that renal insufficiency/failure is chronic?
* Anemia
* Hypocalcemia or WRI (dogs, cats, ruminants)
* Hypercalcemia (equids)
* clinical findings including duration of signs
56
What is Acute Renal failure?
* Abrupt insult or disease
* Marked decrease in GFR ⇢ Azotemia ⇢ uremia
* degree of azotemia does not differentiate chronic vs acute
* rate of increase of UN & Crt more rapid in acute disease
* Reversible or Irreversible
57
What happens to urine volume and USG during acute renal failure?
* **Volume**:
* Kidneys may filter little blood ⇢ **oliguria or anuria**
* No time for compensatory hypertrophy of healthy nephrons
* **USG**:
* Variable
* **Concentrated** - if formed prior to insult
* **Isosthenuric** - no ability to concentrate or dilute
* Not expected to be hyposthenuric
58
What is Hemorrhagic/Inflammatory proteinuria?
* **Most common** mechanism for additional protein in urine
* **Hemorrhage** anywhere in the Urinary tract
* **Inflammation** causing **exudation of plasma proteins** into the urinary tract
* Magnitude varies but it does NOT lead to hypoalbuminemia
59
What is Functional proteinuria?
* Transient mild increase in urine protein content
* exercise, fever, seizures, stress
* mechanism unclear
60
What is Overload proteinuria?
* increased plasma concentration of small proteins that pass through glomerular filtration barrier and exceed capacity for tubular resorption
* Hemoglobin, myoglobin, immunoglobulin light chains (Bence Jones proteins)
* Does NOT lead to hypoproteinemia
61
What is Tubular proteinuria?
* Proximal tubular injury causing failure to resorb small proteins
* Usually associated with acute renal tubule damage
* nephrotoxic agent or ischemia
* Does NOT result in hypoproteinemia
62
What is Glomerular proteinuria?
* **Damage/disruption of the glomerular filtration barrier**
* immune complex deposition
* Amyloid deposition
* Inflammatory cells contribute - release cytokines and other mediators that can damage the glomerulus
* **Increased permeability t**o large and/or negatively charged proteins
* **Albumin** first, globulins later with progressive damage
* Damage often leads to selective hypoproteinemia
* Progressive disease can lead to:
* tubular damage and tubular proteinuria, loss of nephrons ⇢ azotemia, renal failure
* Leads to **Selective Hypoproteinemia**
63
What happens with severe glomerular damage?
* With sever glomerular damage - entire nephron may become non-functional
* if many nephrons are lost - signs of renal failure
* azotemia, uremia, isosthenuria, acidemia, etc
64
What is Nephrotic syndrome?
* Severe, persistent proteinuria
* Hypoproteinemia (loss of many proteins)
* Hypercholesterolemia
* Ascites or edema (decreased plasma oncotic pressure)
65
What are the Pre and Post renal sources of Proteinuria?
* **Hemorrhage** - red/red-brown, turbid urine _with RBCs_ in sediment
* **Hemoglobinuria** - red/red-brown urine, no RBCs in sediment, _red/red-brown plasma, anemia_
* **Myoglobinuria** - red/red-brown urine, no RBCs, plasma normal color, not anemic, _signs of severe muscle damage,_ increased CK
* **Inflammation -**_WBCs_ in sediment
66
When should Glomerular disease be suspected when interpreting Urine Protein Assays (Dipstick)?
* When there is no evidence of non-glomerular sources of proteinuria AND:
* 1+ protein in dilute urine (USG \< 1.012)
* ≥2+ protein in concentrated urine
* And/or hypoalbuminemia with no other cause present
67
What is the Urine Protein : Urine Creatinine Ratio (UPC)?
* An index of the amount of protein regardless of urine concentration
* Measured in a single urine sample
* most useful when pre- and postrenal sources of protein have been ruled out
* Will be Increased with any increase in protein
68
What are the different UPC ratios and their interpretations?
* UPC \< 0.2: healthy dogs/cats
* UPC 0.1 - 0.4 (cats) 0.1 - 0.5 (dogs): borderline
* not conclusive evidence of proteinuric renal disease
* UPC 0.4 - 3.0 (C) 0.5 - 3.0 (D): proteinuria present
* could result from glomerular or tubular disease
* UPC \> 3.0 - glomerular disease
* tubular disease may also be present, but it is not the only one
* UPC ~15+ : most indicative of amyloidosis
Clinical Pathology
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