The Normal Glomerular Filtration Rate (GFR):

There is considerable variation between normal individuals with regard to renal size and the overall nephron mass which are determined by not only genetic predisposition but nutritional factors and indeed perinatal exposures. (1) Clearly these factors will influence the measured baseline renal characteristics. The most widely used measure of kidney function is the GFR. The glomerular filtration rate describes the volume of fluid filtered from the glomerular capillaries into the Bowman’s capsule per unit time. This is maintained by the difference in tone of the afferent and efferent hence the filtration rate is dependent on this pressure differential created through vasoconstriction of the input or afferent arteriole versus the lower blood pressure created by vasodilation of the output or efferent arteriole. It follows that when any solute is freely filtered and neither reabsorbed nor secreted by the kidneys then the GFR will equal the clearance rate of that solute. The GFR is calculated from the quantity of the substance in the urine that originated from a calculable volume of blood over unit time. Where the serum creatinine is measured this is expressed simply as:

Therefore, the product of the urinary creatinine concentration and urine flow equals the amount of creatinine excreted during the time that urine has been collected. This equals the creatinine filtered at the glomerulus assuming free filtration and no reabsorption in the nephron. If we divide this value mass by the plasma concentration of creatinine this equates to the volume of plasma fluid that has entered Bowman’s capsule within the time period studied and hence the GFR is recorded in units of volume per time e.g.’ mL/min. Although creatinine, a breakdown product of creatine phosphate, is commonly used as it is freely filtered by the glomerulus it is not a perfect monitor of the GFR as it is also actively secreted by the peritubular capillaries. This can lead to an overestimation of the GFR of between 10-20%. Other methods, such as inulin clearance are more accurate but time consuming and are employed mainly as research tools. A number of formulae have been described which estimate the GFR, or specifically, the creatinine clearance, based on serum creatinine levels. One of the most commonly used is the Modification of Diet in Renal Disease Study Group (MDRD) equation. (2) The original equation used 6 variables: serum creatinine, age, ethnicity, gender, albumin and urea levels. However, the most commonly employed is the 4-variable MDRD which does not use urea or albumin levels. Importantly, these equations tend to underestimate the GFR in normal subjects and have not been validated in acute kidney injury (AKI).

Although the GFR is stable it does vary with age with a decline in GFR by 0.8ml/min/1.73m2/year with the rate of decline being lower in males. (3) Of note, the equations for estimating GFR are not validated in AKI and this is because the serum creatinine and the GFR remain within the normal range even in the presence of significant renal damage. Indeed, the baseline GFR may not change until 50% of nephrons are lost and therefore employing the GFR in AKI is of little use as significant damage may have occurred and gone undetected using conventional means. (4) Therefore, as a sensitive measure of early detection of renal disease the GFR is far from being a “gold-standard” and attempts have been made to assess kidney function in a more dynamic fashion.

What is the Functional Renal Reserve (FRR)?

Although GFR as measured by creatinine clearance in any individual is relatively consistent over longer periods of time, acute changes in GFR is also well recognised and can be triggered by a variety of precipitants. Indeed, this was first described in 1923 where increases in urea excretion in humans were noted following administration of food, caffeine and glutamic acid and reduced by exercise and, in rabbits, large doses of adrenaline. (5) Since this initial description it has been consistently demonstrated that the GFR rises following a meal of animal protein or indeed an infusion of amino acids. (6, 7) This rise in GFR was initially regarded as a reserve upon which the kidney could utilise when needed: the so-called functional renal reserve (FRR). This lead to a somewhat simplistic view that when the kidney was damaged, or filtration capacity was lost then the reserve may be employed initially to preserve function. As a consequence, depletion of the renal reserve would occur before loss of significant basal GFR and hence before the onset of chronic kidney disease (CKD). Therefore it was thought that measuring the FRR may provide an early indicator of renal impairment and would follow that once the renal reserve was “exhausted” then further insults would lead to CKD. (6) However, as expected the reality is somewhat more complex. The GFR response is not lost in disease states and the response therefore is not a true “reserve” and also the mechanisms of the increased GFR differ depending on the stimulus. However, it is clear that the normal kidney does not “function” at its maximal capacity and may adapt to “stress” through a hyperfiltration response. The absolute value of this response will be dictated, in part, by the underlying GFR and therefore in disease states one may not exhibit such a marked response. This may be viewed as an adaptive mechanism to a change in metabolism through, in the case of diet, nitrogenous solute load. The mechanism behind this response is that of glomerular hyperfiltration.

Glomerular hyperfiltration

The absolute increase in GFR in healthy individuals following protein loading is driven by glomerular hyperfiltration. (8) Conventionally, glomerular hyperfiltration is defined as a GFR > 2 standard deviations above the mean whole-kidney GFR. Under conditions of protein loading the increase in GFR is mediated through renal kallikrein and other vasoactive kinins as well as increased generation of nitric oxide. (9) Interestingly, glomerular hyperfiltration itself may cause renal injury through intraglomerular hypertension mediating further damage. Indeed, glomerular hyperfiltration may contribute to the progression of several chronic renal conditions. These include adult polycystic kidney disease, focal segmental glomerulosclerosis and diabetes. Of course, it may also reflect a normal response, with glomerular hyperfiltration seen in the pregnant state due to an increase in renal plasma flow in association with decreased vascular resistance, stimulation of the renin-angiotensin system and retention of sodium and water. The increased blood flow seems to be the major drive for the glomerular hyperfiltration with no evidence of glomerular hypertension or chronic damage. (10)

Glomerular hyperfiltration may be through increased whole-kidney GFR but may also, particularly in disease states, as what is termed single nephron GFR. This is usually a compensatory response to a reduction in functioning renal mass. However, in pregnancy or following protein loading there appears to be an increase in GFR without glomerular hypertension and no chronic glomerular damage.

The relevance of FRR to AKI: “Sub-clinical” damage

Clearly the use of the GFR is inadequate in terms of assessing damage but with the advent of many new markers of renal damage different end points may be established. To-date, most studies using biomarkers have concentrated on the ability of the biomarker to predict either changes in serum creatinine or urine output as these are the features that define AKI under the current guidelines. (11-13) However, in several studies the presence of a positive biomarker where conventional markers of AKI have not proved diagnostic is associated with worse outcomes. This implies that renal injury may have occurred occultly leading to the term sub-clinical AKI. (14) It follows that such “damage” may be discovered using different techniques for assessing renal function. Indeed, a recent investigation in patients undergoing elective cardiac surgery examined the preoperative FRR by using a high protein load test. (15) The primary endpoint was the ability of the FRR to predict AKI within 7 days of operation. 13.6& of patients developed AKI and the FRR was lower in those who subsequently developed AKI (p = <0.001). Moreover, patients with an FRR of < 15 ml/min were nearly 12 times more likely to develop AKI. Thus, the lower FRR is clearly a risk factor for the development of AKI.


The FRR is clearly an important measure and when reduced seems to increase the risk of AKI following insult. It may well be that patients with positive biomarkers following insult who do not exhibit AKI may suffer a reduction in there FRR. In turn, this may well put the patient at risk of AKI following further insult. In the era of biomarkers, we do not examine renal function in great depth. When we do we may find that there is no such thing as a negative biomarker for AKI.


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Lui G Forni
Intensive Care Unit, Royal Surrey County Hospital NHS Foundation Trust,
Egerton Road, Guildford, UK, GU2 7XX

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