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CPR102: Biochemical investigation of urogenital di


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Filtration size limit
Filtration through the glomerular membrane is dependent on molecular size with a cutoff between 20 - 40 A, corresponding to a protein molecular mass about 30 – 70 kDa
Filtration charge limit
Negatively charged molecules have lower permeability
Protein filtration
Small proteins like ß2-microglobulin (13.5 kDa) and Lysozyme (11.5 kDa) are freely filtered but they are almost completely reabsorbed in the proximal tubules
Protein excretion
Normal daily excretion < 150 mg; about 40 - 50% is Albumin (67 kDa) but the proportion of Albumin increases with increasing severity of proteinuria, e.g., 70% with proteinuria > 1000 mg/L
Glomerular proteinuria causes
Increased glomerular permeability
Glomerular proteinuria type of proteins
Progressively increasing excretion of higher molecular weight proteins as permeability increases (e.g. albumin, IgG)
Tubular proteinuria causes
PCT damage, ↓nephron number, DCT damage
PCT damage proteinuria causes
decreased tubular reabsorptive capacity and/or release of intracellular components (e.g. due to nephrotoxic drugs or toxins causing tubular damage)
PCT damage proteinuria type of proteins
Alpha 1-Microglobulin, Beta 2-Microglobulin, Retinol binding protein (RBP)
↓nephron number proteinuria causes
increased filtered load per nephron
↓nephron number proteinuria type of protein
Same as PCT
DCT damage proteinuria type of protein
Tamm-Horsfall glycoprotein, pi-Glutathione-S-transferase
Overflow proteinuria causes
Increased plasma concentration of relatively freely filtered proteins
Overflow proteinuria type of proteins
Bence Jones protein (BJP), Lysozyme, Myoglobin
Orthostatic proteinuria
Protein excretion varies with posture, increasing on standing. Orthostatic proteinuria present in about 10 - 20% healthy subjects at prolonged upright posture; remits if the subject remains recumbent
Transient proteinuria
Mild to moderate proteinuria may be found in systemic illnesses apparently not related to the kidneys, e.g., high fever, congestive heart failure, and seizures. Transient proteinuria may also be found in healthy athletes after strenuous exercise and often in UTI. Transient proteinuria is a common phenomenon affecting 4% of men and 7% of women
Urinary protein measurement indication(1)
Newly discovered raised serum creatinine / reduced GFR, Newly discovered haematuria (esp. microscopic haematuria)
Urinary protein measurement indication(2)
Assessment of severity of known kidney disease, Initial assessment of patients with HT or newly diagnosed T2DM
Urinary protein measurement indication(3)
Unexplained oedema, Suspected multisystem disease, e.g., SLE
Urinary protein measurement indication(4)
Family history of stage 5 CKD or hereditary kidney disease, Structural renal tract disease, recurrent renal calculi
Urine protein Specimen Timed collection
24-hour, 12-hour overnight, 4-hour
Urine protein Specimen random
Urine Protein / Creatinine ratio with random sample (gradually replacing the tedious and error-prone timed collected sample approach in most circumstances)
Dipstick methods for Urine Protein uses
Most sensitive to albumin, Poor method for detecting tubular proteinuria
Dipstick methods for Urine Protein content
The reagent strip test for total protein includes a cellulose test pad impregnated with tetrabromphenol blue and a citrate pH 3 buffer
Dipstick methods color change
Yellow -> green (protein)
Dipstick methods for Urine Protein limitation
The reagent is most sensitive to albumin and less sensitive to globulins, Bence Jones protein, mucoproteins, and hemoglobin
Specimens for urine total protein
Timed (24-hour or 12-hour) urine specimens OR Spot urine specimen
Timed (24-hour or 12-hour) urine specimens
The entire volume of urine produced in a specified time period is collected
Timed Specimens for urine total protein procedure
A 24-hour urine sample should be collected into a clean, plain container. The first void of the day should be discarded and then all urine passed in the next 24 hours collected
Timed Specimens for urine total protein Disadvantages
inconvenient for patients, significant inaccuracies due to incomplete collection of all urine voided, timing errors and appreciable intra-individual variation due to varying activity, hydration and diet
Spot urine specimen
A collection from a single episode of passing urine, which need
Spot specimens specification
A first morning spot specimen is the first urine passed after waking in the morning, A random spot specimen is one where the time of day is not specified
Spot specimens precaution
Since urinary protein excretion follows a circadian pattern and tends to be highest in the afternoon, UACR tests are most accurate when performed on early morning (first-void) urine specimens
Spot urine Pr/Cr ratio (UACR/UPCR)
a convenient, user-friendly and reliable method to replace 24-hour urine protein measurement for the assessment of proteinuria
Underestimation of UPCR
In individuals with large muscle mass, in whom creatinine excretion may be much higher than average population
Overestimation of UPCR
In a cachectic patient or a patient with small muscle mass, in whom creatinine excretion may be much lower than average population
Microalbuminuria
increase in urinary excretion of albumin above the reference interval for healthy nondiabetic subjects, but at an excretion that is not generally detectable by less sensitive clinical tests such as reagent strips designed to measure total protein
Urine Albumin
primarily measured as a marker of the risk of development of renal damage in diabetic patients.
elevated urine albumin
established marker of cardiovascular risk in the diabetic and nondiabetic populations
Microalbuminuria and macro
To be consistent with newer nomenclature intended to emphasize the continuous nature of albuminuria as a risk factor, the terms “microalbuminuria” (30–299 mg/24 h) and “macroalbuminuria” (>300 mg/24 h) will no longer be used, but rather referred to as persistent albuminuria at levels 30–299 mg/24 h and levels ≥300 mg/24 h. Normal albumin excretion is currently defined as <30 mg/24 h.
Urine albumin summary
Albumin (Mr 66 kDa) is predominantly retained in the circulation by the glomerular basement membrane due to its size and negative charge
Urine albumin caution
Due to high biological variability and nonrenal influences, albuminuria should be confirmed on at least two occasions
Urine albumin in healthy people
In health, only small amounts of albumin are filtered. This is largely reabsorbed in the PCT
Urine albumin uses
Measurement of the albumin-to-creatinine ratio (ACR) allows the use of a spot sample with correction for variations in urinary concentration in an individual
Nephrotic Syndrome
triad of heavy proteinuria, hypoalbuminemia, and edema, Associated with hyperlipoproteinaemia or Glomerular diseases due to e.g., diabetes, SLE, glomerulonephritis, heavy metal toxicity (e.g., mercury, gold)
Nephrotic Syndrome range
Proteinuria > 3.5 g/day/1.73 m2
Myoglobulinuria
Red-brown colour urine
Myoglobulinuria etiology
In rhabdomyolysis, large amounts of myoglobin are released into the plasma, saturating the tubular reabsorptive mechanism
Myoglobin
is a small (17.8 kDa), heme-containing protein normally catabolized by endocytosis and proteolysis in the proximal tubule following glomerular filtration
Myoglobin effect
directly toxic to the renal tubules and can cause acute tubular necrosis with acute kidney injury
Myoglobulinuria Ix
a positive reaction with hemoglobin reagent strip tests
Myoglobulinuria Dx
plasma creatine kinase, urine myoglobin
Renal Stone Analysis
Targeted therapeutic intervention and medical prophylaxis for recurrence require reliable information on stone type, its chemical composition
Recurrent Renal Stones high risk conditions
Highly recurrent stone formation (≥3 stones in 3 yrs), Residual stone fragments (3 mo after stone therapy), Infection stones, Uric acid and urate stones (gout), Brushite stones (calcium hydrogen phosphate), Hyperparathyroidis, Nephrocalcinosis, Bilateral vast stone burden, GI diseases (Crohn’s disease, malabsorption, colitis), Solitary kidney
Recurrent Renal Stones high risk groups
Children and teenagers, Family history of stones, Genetic determined stones (rare)
Role of Renal Stone Analysis
To assist with identification of risk factors for targeted treatment that aims to prevent recurrence of renal calculi, changes in RF, & epidemiological trends
Types of Renal Stone
Calcium Phosphate/Carbonate, Magnesium, Ammonium and Phosphate (Struvite stones), Calcium Oxalate, Uric acid, Cystine
Calcium Phosphate/Carbonate
may be a consequence of primary hyperparathyroidism or renal tubular acidosis, excess Ca ingestion or idiopathic
Stones)
often associated with urinary tract infections with urease-producing organisms (e.g., staghorn calculus)
Calcium Oxalate
commonest, aetiology often obscure; often associated with idiopathic hypercalciuria, intermittent hyperoxaluria, low urinary citrate, or rarely primary hyperoxaluria
Uric acid
may be a consequence of hyperuricaemia, Gout/ idiopathic
Cystine
very rare, associated with cystinuria
First time urine stone prevalence
Calcium Oxalate > Calcium phosphate > Uric acid > Struvite
Recurrent urine stone prevalence
Calcium Oxalate > Calcium phosphate > Uric acid > Cystine >Struvite
calculus
With the advent of infrared spectroscopic study and diffraction crystallography
Lab test Blood
Blood Ca, Pi, HCO3, Cr, ALP,
Random Early morning sample
pH, AA, Microscopy, bacterial culture
24-hour urine
2 or more 24-hour urine collected while patients are on their usual diet, looking at volume, creatinine, sodium, calcium, phosphate, oxalate, urate and citrate
PTH level and acid loading test
for selected patients (e.g., suspected primary hyperparathyroidism, RTA)