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CPR101: Biochemical investigation of urogenital di


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Renal Blood Flow (RBF)
1200mL/min (~20% CO)
GFR
125 mL/min (Filtration Fraction ~ 20%)
Urine Formation
~ 1.5 L/day, 1 mL/min
Water reabosrption
~ 99% H2O in glomerular ultrafiltrate reabsorbed by the kidney with~ 65% occurs in the proximal renal tubules accompanied by Na+ and
Waste product metabolism
~ 550 mOsm/day
Maximal Urinary Concentration attainable
1,300 – 1,400 mOsm/L
Minimal Volume of Urine Water
400 mL/day
Azotaemia
inevitable with daily Urinary Output < 400 mL
GFR
Volume of fluid filtered from the kidney glomerular capillaries into the Bowman’s capsule per unit time, often expressed in mL/min
Clearance
the volume of plasma from which that substance is completely cleared by the kidneys per unit time.
An ideal substance for GFR estimation
Freely filtered at the glomerulus, Not reabsorbed by the renal tubules, Not secreted by the renal tubules or other organs of the body, Not synthesized or metabolized by the renal tubules
GFR significance
Index of CKD, decreasing GFR precedes renal failure, monitor progression of renal disease, predictor of onset of renal failure, and for proper dosing of drugs
Inulin limitation
it requires infusion of the polysaccharide at a continuous and constant rate for several hours, which is inconvenient and costly
Creatinine
metabolic end-product of skeletal muscle Creatine, and is released into the blood at a relatively sconstant rate
Creatinine problem
Creatinine is secreted by the renal tubules into the glomerular filtrate where %tubular secretion increases with rising blood levels – tends to overestimate the true GFR
GFR by Cr
GFR = Constant / Plasma Creatinine, Plasma CREATININE is inversely related to GFR
Cr limitation
Inability to detect mild to moderate reduction in GFR – GFR often decreases by ~40-50% before plasma Creatinine is raised above upper normal limits
Cr variation
Age, gender and ethnic-related difference in production related to muscle mass
Cr Ix
A rise in blood Creatinine of ≥ 20% from previous levels, especially in the acute setting, should trigger investigations as to the cause even if the Creatinine level still remains within the reference interval
Cr interaction with drugs
The presence of certain drugs may increase the level of the serum creatinine by decreasing creatinine secretion (e.g. trimethoprim, H2-blocker cimetidine)
Cr analytical interference
very high level of bilirubin and acetoacetate lead to spuriously low and high creatinine results respectively due to analytical interferences
Cr requirement for stable kidney function
Early in the course of acute kidney injury, for example, the GFR is markedly reduced, but there has not yet been time for the filtration marker to accumulate and, therefore, for the filtration marker to reflect the degree of kidney disease severity i.e. Glomerular filtration rate (GFR) may fall considerably before serum creatinine is significantly increased.
Plasma UREA levels
Urea is a waste product of amino acid metabolism, synthesized by the liver from ammonia and CO2
Excretory load of urea
dependent on amino acid and protein intake as well as net body protein metabolism (increased catabolism results in raised urea levels due to accelerated protein breakdown, e.g., Cushing syndrome, severe burn)
Urea diffusion
Filtered freely by the glomeruli and readily diffuses back into the circulation through renal tubular membrane by a passive process down the concentration gradient
Urea clearance
dependent on Urine Flow Rate
Synthesis of urea
NH4 + CO2 -> Carbamoyl Phosphate -> L-citrulline (+Aspartate) -> Argininosuccinate -> L-arginine (remove fumarate) -> Urea
Urea as a poor indicator of GFR (1)
↓ production (low protein intake) can lower the blood [UREA] sufficiently to enable a normal plasma / serum level to be associated with significant renal insufficiency
Urea as a poor indicator of GFR (2)
GFR has to drop ~ 40% before the blood [UREA] begins to rise above normal upper limit
Urea as a poor indicator of GFR (3)
↑production (eg. high protein intake) in the face of minor degrees of renal impairment can result in disproportionately high blood [UREA]
Factors increasing Urea
High protein diet, GIB, Tissue Trauma, Glucocorticoids, Tetracycline
Factors decreasing Urea
Liver disease, malnutrition
Renal Function Test
measurement of Creatinine and Urea conc in serum or plasma (also Na+, K+, Cl-, HCO3-)
Condition for clearance = GFR
Freely filtered by glomerulus and not reabsorbed or secreted by the renal tubules & Kidney = sole route of excretion from the body (i.e. no
Calculation of Cr Cl
CrCl = U*V/P, V of urine produced over a fixed period (usually a 24-hour collection)
CrCl problem
24-hour urine collection is inconvenient and error-prone, Accuracy undermined by error in the timing of 24-hour urine collection (e.g., incomplete collection will underestimate CrCl), Measurement Uncertainty may be up to 30%
CrCl pros
More reliable than formula-predicted GFR in some circumstances
GFR by Prediction Formulae
Cockroft & Gault Formula / MDRD Formula (gaining popularity)
Cockroft & Gault Formula
CrCl= (140-age)* BW in kg *0.85(female)/ (0.814*P[Cr])
Cockroft & Gault Formula factors to better correlate
Plasma [Cr] is not within normal range, Renal impairment is not severe and relatively stable, No inhibition of tubular secretion of creatinine by medications
Cockroft & Gault Formula problem
Tend to overestimate GFR in advanced renal failure
Cockroft & Gault Formula limitations
Developed from only 249 subjects, only 9 female & Information on patient’s weight is not available for most clinical laboratories
MDRD Formula
186# x (Pcr)^-1.154 x (Age)^-0.203 x 0.742 (female) x 1.210*, # with newer assay, * African-american
MDRD Formula vs C&G
GFR vs CrCl
MDRD Formula validation
Validated against a reference method for GFR measurement based on renal clearance of 125I-iothalamate
MDRD Formula pros
Does not require body weight and a timed urine sample
MDRD Formula acuuracy
More accurate than other equations tested, especially at GFR < 60 mL/min/1.73m2 (but tends to underestimate eGFR in subjects with GFR > 60 mL/min/1.73m2 )
MDRD Formula problem
NOT extensively evaluated in those with normal renal function, Not validated in subjects <18 and >70 yrs, pregnant women
CKD-EPI formula (2009)
improved accuracy and reduced bias at GFR > 60 mL/min/1.73m2
CKD-EPI formula (2009) equation
eGFR= 141*min(SCr/k,1)^a * max(SCr/k,1)^-1.209* 0.993^age*[1.018 if female]* [1.159 if black], k=0.7(F), 0.9(M), a= -0.329(F), -0.411(M)
CKD-EPI formula vs MDRD
CKD-EPI was shown to be as accurate as MDRD formula in eGFR less than 60ml/min/1.73m2 and much less bias at eGFR greater than 60ml/min/1.73m2
Schwartz formula use
for estimation of GFR in Children, Employs serum Creatinine (mg/dL), child’s height (cm) and a Constant (k) to estimate the GFR
Schwartz formula
eGFR= k* height/ SCr, where k is a constant that depends on muscle mass, which itself varies with a child's age.
CKD definition
abnormalities of kidney structure or function, present for >3 months, with implications for health
Markers of kidney damage
Albuminuria >30 mg/day, Urine sediment abnormalities, Electrolyte and other abnormalities caused by tubular disorders, Pathologic abnormalities, Imaging abnormalities, History of kidney transplantation
CKD stage 1 (>90)
CKD only if other signs of kidney damage, e.g. proteinuria, haematuria, or scarred kidneys seen on imaging
CKD stage 2 (60-89)
CKD only if other signs of kidney damage, e.g. proteinuria, haematuria, or scarred kidneys seen on imaging
CKD stage 3 (30-59)
CKD if persistent for ≥ 3 months
CKD stage 4 (15-29)
CKD if persistent for ≥ 3 months
CKD stage 5 (<15)
CKD if persistent for ≥ 3 months
Formula application
Only apply in steady state(Stable renal function for 4 days); not good for Acute RF
Plasma Cr changes
“Goulash effect”: 80% rise in creatinine after 300g of cooked beef, Less variability in early morning creatinine, Strenuous exercise may increase creatinine by 14%
Plasma Cr changes with diseases
liver disease & profound hyperbilirubinaemia
Plasma Cr changes with drugs
Drugs inhibiting tubular creatinine secretion can raise creatinine conc (e.g., trimethoprim, cimetidine, probenecid, amiloride, triamterine, spironolactione, etc).
Clearance measurement necessary for eGFR conditions
Extremes of age, Extremes of body habitus (e.g., obesity, low body mass index <18.5), Severe malnutrition, cachexia and inanition (cirrhosis, end-stage renal failure), Grossly abnormal muscle mass (amputation, tetraplegia), High or low intake of creatinine or creatine (vegetarian diet,
eGFR by CKD-EPI & related formulae summary
Most readily available result; increasing application in drug-dosing decision
Cockroft & Gault formula summary
Widely accepted for drug-dosing decisions
Creatinine Clearance by timed urine collection summary
For extremes of body composition, Faulty and inaccurate timing of urine
GFR measured by infusion studies summary
“Gold standard” Expensive and time-consuming, and not practicable in most clinical settings, mainly reserved for research
Cystatin C
Cysteine protease inhibitor, Low MW (~13 KD) non-glycosylated basic protein
Cystatin C synthesis
Synthesized by all nucleated cells and produced at a constant rate, Not affected by muscle mass, gender and diet
Cystatin C associated diseases
A modest increase in production is seen in obesity, hyperthyroidism, and inflammation
Cystatin C elimination
Cystatin C is removed from the circulation by the kidneys, No extra-renal routes of elimination, Freely filtered at glomeruluu, Reabsorbed and metabolized by proximal tubules with only a minute amount present in urine
Cystatin C clinical significance
Increases in urinary excretion may be a marker for proximal renal tubule injury or dysfunction
Cystatin C development
Cystatin C-based formulae for GFR estimation have been developed
Cystatin C limitation
Wider clinical application hampered the relatively high assay cost, Assay not widely available.