L80: Biochemical Investigation Of Urogenital Disease 1 Flashcards
Functions of kidneys
- Filtration + Reabsorption
- Homeostasis: volume, BP, acid-base, electrolyte
- Metabolic:
—> synthetic: glutathione, glyconeogenesis, ammonia
—> catabolic: hormones, cytokines - Endocrine: Erythropoietin synthesis, Vitamin D activation, Renin
Physiological parameter
Renal blood flow: 1.2 L/min (~20% CO)
GFR: 125 ml/min
Filtration fraction: GFR/renal plasma flow
Reabsorption: 99% water reabsorbed, 65% proximal tubules accompanied by Na, Cl reabsorption
Urine formation: 1.5 L/day, 1 ml/min
—> Azotaemia is inevitable with urinary output < 400 ml/day
GFR
GFR: volume of filtrate produced by kidneys per time
Require: - adequate nephron number - intact glomerular function - normal renal perfusion —> ↓ GFR —> ↑ in Creatinine + Urea + Electrolyte + Acid-base imbalance
GFR x Plasma conc = Urine formation rate x urine conc
—> GFR = V x U / P
—> rate of excretion ∝ GFR (if freely filtered, not reabsorbed, secreted, synthesised)
Renal clearance
Renal clearance: volume of plasma in which substance is cleared by kidney per time
Creatinine as estimate of GFR
- Metabolic end product of muscle creatine
- not protein bound, small, non-polar
- freely filtered, slightly secreted
- not metabolised
- constant plasma concentration
- **- Plasma and Urine creatinine concentration readily available
***Steady state:
Creatinine filtered = Creatinine excreted = constant
—> GFR x Plasma creatinine conc = Constant
—> GFR inversely proportional to Plasma creatinine conc
***Limitations of creatinine
- Inability to detect mild to moderate reduction in GFR
—> Plasma creatinine raised above upper limit only after GFR decreases by 40-50% - Age, gender, diet, ethnic difference in production
—> Reduction in muscle mass can mask diseased kidneys since creatinine level is low + low excretion —> normal plasma creatinine level - Between-subject variation up to 13%
—> ↑ in creatinine > 20% should trigger investigations even though within reference intervals - Requirement for stable kidney function
—> acute kidney injury: filtration marker slow increase in response to GFR reduction
—> Secretion become more significant as blood levels rise
—> drugs can ↑ level of serum creatinine by decreasing secretion
—> analytical interference (very high bilirubin, acetoacetate
Plasma urea level as estimate of GFR
- waste product of amino acid metabolism
- synthesised from ammonia + CO2
- Excretory load depends on
—> amino acid / protein intake
—> nets body protein metabolism (↑ catabolism due to accelerated protein breakdown e.g. Cushing syndrome)
***- Filtered freely but readily diffuses back into circulation through renal tubules
—> Clearance depends on URINE FLOW RATE (high UFR —> little diffusion)
Limitations of plasma Urea level
- Low protein intake (↓ urea production) can mask renal insufficiency by a normal [urea] level (~ to creatinine)
- High protein intake (↑ urea production) can cause disproportionally high [urea] in minor renal impairment
- GFR has to drop to 40% before [urea] begins to rise
- Filtered freely but readily diffuses back into circulation through renal tubules
—> Clearance depends on URINE FLOW RATE (high UFR —> little diffusion)
Factors affecting urea level
↑ Urea:
- high protein diet
- GI bleeding
- tissue trauma
- glucocorticoid
- tetracycline
↓ Urea:
- liver disease
- malnutrition
Renal function test
- Comprises measurement of Creatinine + Urea plasma concentration
- Convenient but insensitive of glomerular function
- levels stay within normal range despite significant ↓ GFR
- Subject to various factors affecting blood levels
Creatinine Clearance
Creatinine Clearance = Ucr x V / Pcr (same as GFR equation)
—> creatinine clearance used to estimate true GFR
—> creatinine clearance > true GFR since creatinine is secreted as well
Advantages
- more reliable than formula-predicted GFR in some circumstances
Disadvantages
- 24 hour urine collection is inconvenient and error prone
- Error in timing of 24 hour urine collection (incomplete collection of urine will underestimate CrCl)
- measurement uncertainty up to 30%
Cockcroft and Gault equation pros and cons
CrCl = gender constant x (140-age) x body weight / 0.814 x plasma [creatinine]
Advantage: correlates better with measured GFR values when
- Plasma [creatinine] is not within normal range
- Renal impairment is not severe and relatively stable
- No inhibition of tubular secretion of creatinine by medication
Disadvantage:
- an estimate of CrCl instead of GFR —> positive bias (overestimation) due to renal tubular secretion
- information on weight might not be available
- weight tend to overestimate GFR in advanced renal failure
- developed from only 249 subjects, all subjects had CKD
MDRD formula pros and cons
Advantage
- Calculate GFR —> Estimates GFR rather than creatinine clearance
- validated against reference method for GFR measurement based on renal clearance of 125-I-iothalamate
- predict GFR over wide range of values adjusted for body size
- do not require weight
- do not require urine sample
- more accurate than other equations tested, esp. at GFR < 60
- extensively evaluated in subjects with varying degree of renal insufficiency
Disadvantage:
- underestimate GFR >60 (negative bias)
- not evaluated in subjects with normal renal function
- not validated in subjects <18 and >70, pregnant women
- findings from different studies conflicting
CKD-EPI formula
Improved over MDRD formula —> as accurate at GFR < 60 —> less underestimation at GFR > 60 —> minimise over-diagnosis of CKD —> better risk prediction —> suggested as equation of choice
Schwartz formula
- For Children
eGFR = k x Height / Serum creatinine
(k is a constant depend on age —> relevant to muscle mass)
- Newer formula incorporate Cystatin C as well to give better estimation of GFR
