Protección del Derecho a la Identidad del niño

8.2.1 Creatinine and the Assessment of Renal Function

Creatinine is a spontaneously formed cyclical derivative of creatine degradation in the tissues. Creatine is synthesised in the liver and to a lesser extent the kidney and enters cells through a membrane transporter system whereby it is utilised to replen-ish ATP stores via phosphocreatine production [3]. Skeletal muscle is the major body reservoir creatine and consequently is the source of the majority of plasma creatinine. As a small (113 Da) basic molecule it is freely filtered in the glomerulus and appears unaltered in the urine with the addition of a small additional contribu-tion from active tubular secrecontribu-tion. As renal excrecontribu-tion is so efficient, extra-renal cre-atinine excretion is also negligible in most conditions. The basis of use of crecre-atinine for assessment of renal function thus relies on its rate of excretion being approxi-mately proportional to GFR. Consequently creatinine excretion approximates to GFR (rate of plasma filtered into the urine) multiplied by the concentration of cre-atinine in the plasma. At steady state (constant plasma crecre-atinine) excretion will equal creatinine generation (Eq. 8.1) so that the GFR is proportional to the recipro-cal of plasma creatinine concentration.

GFR×

[

]

Where [Creat]P is the plasma concentration of creatinine (in μmol/ml) and G the creatinine generation rate in μmol/min.

Thus at steady state a lower GFR will be associated with an higher plasma creati-nine following the relationship: GFR α 1/[Creat]^P – so that, assuming a steady state has been achieved and that G is constant, a halving of GFR will be accompanied by a doubling of plasma creatinine. This relationship forms the basis of the use of fold increase in creatinine from baseline to define severity of AKI in consensus defini-tions based on the original RIFLE criteria as this would reflect fold decrease in GFR.

While changes in plasma creatinine define AKI there are significant limitations to its use, particularly in the critically ill [4, 5]. Firstly, use of plasma creatinine as an indirect measure of the GFR is unreliable outside the steady-state, after an acute change in GFR creatinine will rise or fall until achieving a new steady-state where plasma creatinine reflects the new GFR, this process will take a period of time that is

dependent on both the magnitude of change in GFR and the underlying creatinine generation rate. With large falls in GFR many days may pass before steady-state is achieved and until then creatinine will underestimate severity of renal dysfunction.

Secondly, changes in creatinine production can alter measured plasma creatinine concentration as much as changes in excretion (GFR). For example, creatinine pro-duction will fall if there is a repro-duction in lean body mass, if there is a fall in the dietary intake of creatine, or in the presence of liver disease [6]. As these are all com-mon scenario’s in the intensive care unit and the degree of renal dysfunction may be underestimated in the critically ill if one is solely guided by the creatinine concentra-tion and, similarly, renal recovery after AKI may be significantly overestimated [7, 8]. Importantly, sepsis is associated with reduced creatinine production which may account for the seemingly slow rise in creatinine often observed in patients with septic AKI [4]. However, despite these limitations creatinine is still almost univer-sally employed given the fact that assay is cheap, relatively easy and quick.

8.2.2 Clearance Measurements

Despite the limitations of plasma creatinine, acutely, direct measurement of GFR is not normally performed. GFR can be estimated through the calculation of the clear-ance of a molecule such as creatinine that is freely filtered from the plasma in the glomerulus and excreted unchanged into the urine (Eq. 8.2)

GFR ml Creat

Creat

U P

/ min U

( )

[ ]

[ ]

Where [Creat]U & [Creat]P are the urinary and plasma concentrations of creatinine respectively and Qu is the urine flow rate in ml/min.

Although creatinine clearance is often used to estimate GFR, creatinine is by no means an ideal marker for this purpose. The ideal marker would not only be sensi-tive and specific in detecting small, early, changes in GFR, but would also not be secreted, metabolised or reabsorbed by tubular cells. Furthermore, it would be eas-ily measured and would not be influenced by exogenous compounds. Tubular secre-tion of plasma creatinine can cause creatinine clearance to over-estimate GFR by 10–20 % or more, however competing substances for tubular secretion including some drugs can abolish this effect. The difference between Creatinine Clearance and true GFR has become more apparent since the adoption of more accurate Isotope-Dilution Mass-Spectroscopy (IDMS)-traceable laboratory standards and more accurate and precise enzymatic creatinine assays, as previous measurements un-standardised colorimetric assays tended to over-estimate plasma, but not urinary creatinine by detection of non-creatinine plasma chromogens. As an alternative to creatinine exogenous substances without tubular secretion such as inulin, EDTA (ethylenediaminetetraacetic acid) and iohexol are used to measure GFR occasion-ally, however these are impractical in the everyday acute clinical arena.

8.2.3 Alternatives to Creatinine: Cystatin C and Urea

Urea is a water-soluble low molecular weight by product of protein metabolism, which, like creatinine, exhibits a reciprocal relationship with the GFR. However, as a measure of GFR urea clearance has been superseded principally due to the greater variety of factors which influence both its renal clearance and endogenous produc-tion [9]. The main drawback with using urea as a GFR marker is that the rate of renal clearance is not constant. Under steady-state conditions approximately 50 % of urea is reabsorbed by proximal renal tubular cells so that the urea clearance is around 50 % of GFR, however, in hypovolaemic states, enhanced tubular reabsorp-tion of sodium and water together accompanied by urea may decrease urea clear-ance as a proportion of GFR giving rise to a misleading disproportionate rise in the observed urea concentration. Conversely in advanced chronic or acute kidney dis-ease, or in the presence of diuretic agents, urea clearance may rise as a proportion of GFR, so that increase in urea concentration could somewhat blunted. Urea pro-duction has also highly variable rates as these may be increased such as in high protein intake, catabolic states and gastrointestinal haemorrhage, but may also be reduced in acute or chronic malnutrition and liver disease. Therefore, plasma urea and urea clearance is not recommended for GFR estimation particularly under non- steady state conditions.

Cystatin C is a low molecular weight cysteine proteinase inhibitor synthesised at a relatively constant rate by all nucleated cells and released into plasma [10]. The main catabolic site of the Cystatin C are the proximal renal tubular cells following the almost complete (>99 %) filtration by the glomerulus [11]. Therefore, little or no Cystatin C is present in the urine. As a consequence, the urinary clearance of Cystatin C cannot be determined but any fall in GFR correlates well with a rise in serum Cystatin C concentration and excellent correlation with radionuclide derived measurements of GFR [12]. However the lack of a standardised method for mea-surement has prevented widespread adoption into clinical practice. This is coupled with the observation that the accuracy of measurement is affected by older age, sex, smoking status and raised CRP levels as well as abnormal thyroid function and the use of corticosteroids. Nevertheless, confounders of Cystatin C are likely to be less marked than those of creatinine during acute illness and availability of a stan-dardised assay at an acceptable cost may lead to more widespread uptake of Cystatin c measurement in the future.

8.2.4 Mathematical Estimation of GFR

Several equations have been developed and validated for the estimation of the GFR or Creatinine Clearance. These include the Cockcroft-Gault equation, the four vari-able MDRD (Modification of Diet in Renal Disease Study Group equations Study Equation), the CKD-EPI Creatinine Equation, the CKD-EPI Cystatin C Equation and the CKD-EPI Creatinine-Cystatin C Equation. Many laboratories now quote an eGFR value together with serum creatinine. Although useful it must be remembered that, these estimated GFRs are derived values and not measured variables. At heart

these equations are dependent on the reciprocal relationship between GFR and plasma creatinine at steady state transforming this into a direct GFR estimate by providing what is essentially an estimate of creatinine generation normalised to body surface area for individuals of a given age, sex and racial background. They are thus dependent on a patient firstly, being in steady state between GFR and plasma creatinine and, secondly, having a typical creatinine production for the out-patient populations used to generate these estimates. As neither of these are the case in most of critically ill patients, these formulae are not recommended for use in the acute setting, but rather as a tool for managing chronic kidney disease.

8.3 Urinalysis in AKI