Defining acute renal failure: physiological principles

Claudio Ronco physiological principles

Introduction

Definitions are never “right” or “wrong”. They are sim- ply more or less “useful” for a given purpose. The same is true of the clinical syndrome of acute renal failure (ARF), which is common in the ICU [1, 2]. In many ways, its nature and epidemiology resemble those of other loosely defined ICU syndromes, such as sepsis or ARDS. In this physiological note, however, we wish to focus on how our understanding of renal physiology can be used to guide the definition of ARF.

What are the physiological functions of the kidney?

Many renal functions are shared with other organs (acid- base control with lung; blood pressure control via the re- nin-angiotensin-aldosterone axis with liver, lung and ad- renal glands). Other functions are not routinely measured

(small peptide excretion, tubular metabolism, hormonal production) in the ICU and are not considered clinically important. There are only two physiological functions that are routinely and easily measured in the ICU, which are “unique” to the kidney and which are considered clinically important: the production of urine and the ex- cretion of water soluble waste products of metabolism.

Thus, clinicians have focused on these two aspects of re- nal function to help them define the presence of ARF.

Renal solute excretion: glomerular filtration

Renal solute excretion is the result of glomerular filtra- tion and the glomerular filtration rate (GFR) is a conve- nient and time-honoured way of quantifying renal func- tion. However, GFR varies as a function of normal phys- iology as well as disease. For example, subjects on a vegetarian diet may have a GFR of 45–50 ml/min, while subject on a large animal protein intake may have a GFR of 140–150 ml/min, both with the same normal renal mass [3].

Baseline GFR can be incremented by efferent arterio- lar vasoconstriction or afferent arteriolar vasodilatation or both. Angiotensin converting enzyme (ACE) inhibi- tors induce the opposite effect and reduce filtration frac- tion and GFR [4]. It is not clear what the maximum GFR value can be, but it can be approached with an acute ani- mal protein or amino acid load. The concept of a base- line and maximal GFR in humans has been defined as the “renal functional reserve”. Figure 1 displays a series of examples describing the GFR/functional renal mass domain graph. For the purposes of this illustration, GFR can be considered a continuous function, which is maximal in subjects with 100% renal mass, absent in anephric patients and 50% in subjects with a unilateral nephrectomy.

Patients 1 and 2 have the same renal mass but differ-

ent baseline GFRs owing to different basal protein in-

takes levels. Subject 1 has a GFR of 120 ml/min that can be stimulated to 170 ml/min [3, 4, 5, 6]. Patient 2 is a vegetarian and has a baseline GFR of 65 ml/min that also can be stimulated to 170 ml/min. In other words, the re- nal functional reserve in these two patients is different because they are using their GFR capacity at a different level. Patient 3 has undergone a unilateral nephrectomy.

His baseline GFR corresponds to his maximal GFR un- der unrestricted dietary conditions. If a moderate protein restriction is applied to his diet, his baseline GFR may decrease and some degree of renal functional reserve be- come evident. The same concept is true for patient 4;

however, to restore some functional reserve, severe pro- tein restriction is needed. Thus, baseline GFR does not necessarily correspond to the extent of functioning renal mass and even very careful measurements of GFR will not allow us to define renal function without placing it in the context of maximal capacity. In this regard GFR is not unlike a resting ECG for the kidney. When it is grossly abnormal, renal function is impaired, but when it is normal, a stress test is required. Another approach, is to compare measurements taken over time. Serial mea- surements of GFR may be impractical but surrogates are readily available. Because urea, or blood urea nitrogen (BUN), is such a non-specific indicator of renal function [7] it is a very poor surrogate for GFR and will not be discussed further.

Serum creatinine, its physiology and defining acute renal failure

Creatinine is much more specific at assessing renal func- tion than BUN, but it only loosely corresponds to GFR.

For example, a serum creatinine (S

) of 1.5 mg/dl (133 mol/l) at steady-state, corresponds to a GFR of about 36 ml/min in an 80-year-old white female, but of about 77 ml/min in a 20-year-old black male. Similarly, a serum creatinine of 3.0 mg/dl (265 mol/l) in a patient suspected of having renal impairment would reflect a GFR of 16 ml/min in the elderly female but 35 ml/min in

the young male. In both cases, a doubling of serum creat- inine corresponds to an approximate decrease in GFR of 50% (exactly a 55% decrease in the above example) be- cause there is a linear relationship between GFR and 1/Scr. Thus, while every classification of ARF in the lit- erature relies on some threshold value for serum creati- nine concentration, no single creatinine value corre- sponds to a given GFR across all patients. Therefore, it is the change in creatinine that is clinically and physio- logically useful in determining the presence of ARF.

Unfortunately, like all estimates of GFR (including creatinine clearance), the S

is not an accurate reflection of GFR in the non-steady state condition of ARF. During the evolution of dysfunction, S

will underestimate the degree of dysfunction. Nonetheless, the degree to which S

changes from baseline (and perhaps the rate of change as well) will reflect the change in GFR. S

is easily measured and it is reasonably specific for renal function. Thus, S

is a reasonable approximation of GFR in most patients with normal renal function [8]. Creati- nine is formed from non-enzymatic dehydration of cre- atine in the liver and 98% of the creatine pool is in mus- cle. Critically ill patients may have abnormalities in liver function and markedly decreased muscle mass. Addi- tional factors influencing creatinine production include conditions of increased production such as trauma, fever and immobilisation; and conditions of decreased produc- tion including liver disease, decreased muscle mass and ageing. In addition, tubular re-absorption (“back-leak”) may occur in conditions associated with low urine flow rate. Finally, the volume of distribution (V

) for creati- nine (total body water) influences S

and may be dra- matically increased in critically ill patients and, in the short term, its concentration in plasma can be dramati- cally altered by rapid plasma volume expansion. There is currently no information on extra-renal creatinine clear- ance in ARF and a non-steady state condition often ex- ists [9].

Creatinine clearance

Once GFR has reached a steady state it can be quantified

by measuring a 24-h creatinine clearance. Unfortunately,

the accuracy of a creatinine clearance (even when collec-

tion is complete) is limited because as GFR falls, creati-

nine secretion is increased, and thus the rise in S

is less

[10, 11]. Accordingly, creatinine excretion is much

greater than the filtered load, causing overestimation of

the GFR [11]. Therefore creatinine clearance represents

the upper limit of true GFR. A more accurate determina-

tion of GFR would require measurement of the clearance

of inulin or radio-labelled compounds [12]. Unfortunate-

ly, these tests are not routinely available. However, for

clinical purposes, determining the exact GFR is rarely

necessary. Instead, it is important to determine whether

Fig. 1

renal function is stable or getting worse or better. This can usually be determined by monitoring S

alone [8].

Other markers of renal failure

Urine output

Urine output is the commonly measured parameter of re- nal function in the ICU and is more sensitive to changes in renal haemodynamics than biochemical markers of solute clearance. However, it is far less specific—except when severely reduced or absent. Severe ARF can exist despite normal urine output (i.e. non-oliguric ARF) but changes in urine output often occur long before bio- chemical changes are apparent. Since non-oliguric ARF has a lower mortality rate than oliguric ARF, urine out- put is used to differentiate ARF conditions. Classically, oliguria is defined (approximately) as urine output less than 5 ml/kg per day or 0.5 ml/kg per h. It would be highly desirable to have markers which allow physicians to diagnose when oliguria is a true early marker of de- veloping renal failure, because this would allow the identification of patients in whom early intervention may be justified.

Other markers

Kidney injury molecule-1 (KIM-1) expression is mark- edly up-regulated in the proximal tubule in the post- ischemic rat kidney [13]. A soluble form of human KIM-1 can be detected in the urine of patients with ARF and may serve as a useful biomarker for renal proximal tubule injury, possibly facilitating the early diagnosis of the disease and serving to discriminate between different forms of renal dysfunction [13].

Another marker of potential importance is cystatin C (cysC). Cys C is a cysteine proteinase inhibitor of low molecular weight that is produced constantly by nucleat- ed cells (apparently independently of pathological states) and is excreted by the glomerulus, thus closely reflecting GFR. Thus, cysC may be a better marker of GFR than

creatinine [14]. Unfortunately, little information exists on the usefulness of cysC in ARF. A recent pilot study suggested that it might be superior to both S

and the

“modification of diet in renal disease” (MDRD) equation in the detection of ARF [15].

Defining acute renal failure

when baseline renal function is unknown

One option is to calculate a theoretical baseline serum creatinine value for a given patient assuming a normal GFR of approximately 95±20ml/min in women and 120±25 ml/min in men [10]. A normal GFR of approxi- mately 75–100 ml/min per 1.73 m

can be assumed by normalising the GFR to body surface area [16] and, thus, a change from baseline can be estimated for a given pa- tient. The simplified MDRD formula provides a robust estimate of GFR relative to serum creatinine based on age, race and sex [17]. This estimate could then be used to calculate the relative change in GFR in a given pa- tient. The application of the MDRD equation to estimate baseline creatinine requires a simple table with age, race and gender. Table 1 solves the MDRD equation for the lower end of the normal range (i.e. 75 ml/min per 1.73 m

). Note, the MDRD formula is used only to esti- mate the baseline when it is not known. For example, a 50-year-old black female would be expected to have a baseline creatinine of 1.0 mg/dl (88 µmol/l). This ap- proach may misclassify some patients, but is probably adequate for population studies.

Defining acute renal failure in the setting of known renal dysfunction

If the patient has pre-existing renal disease, the baseline GFR and S

will be different from those predicted by the MDRD equation. Also, the relative decrease in renal function required to reach a given level of S

will be less than that of a patient without pre-existing disease. For example, a patient with a S

of 1 mg/dl (88 mol/l) will have a steady-state S

of 3 mg/dl (264 mol/l) when

Table 1 Estimated baseline

creatinine Age Black males White males Black females White females

(years) (mg/dl | µmol/l) (mg/dl | µmol/l) (mg/dl | µmol/l) (mg/dl | µmol/l)

20–24 1.5 | 133 1.3 | 115 1.2 | 106 1.0 | 88

25–29 1.5 |133 1.2 | 106 1.1 | 97 1.0 | 88

30–39 1.4 | 124 1.2 | 106 1.1 | 97 0.9 | 80

40–54 1.3 | 115 1.1 | 97 1.0 | 88 0.9 | 80

55–65 1.3 | 115 1.1 | 97 1.0 | 88 0.8 | 71

>65 1.2 | 106 1.0 | 88 0.9 | 80 0.8 | 71

Estimated glomerular filtration rate (GFR) =75 (ml/min per 1.73 m

) =186x (Scr)–1.154x (age)

0.203x(0.742 if female) x(1.210 if African-American) = exp(5.228 1.154xIn(Scr)–0.203x In(age)

(0.299 if female) +(0.192 if African-American))

75% of GFR is lost. By contrast, when only 50% of GFR is lost in a perfectly matched patient for age, race and sex with a baseline S

of 2.5 mg/dl (221 mol/l), the S

will be 5 mg/dl (442 mol/l). These S

change criteria fail to convey accurately the degree of loss of renal func- tion and the severity of injury. Thus, separate criteria should be used for the diagnosis of ARF superimposed on chronic renal disease. One possible approach would be to use a relative change in S

(e.g. threefold) as the primary criterion for ARF, with an absolute cut-off (e.g.

4 mg/dl or about 350 mol/l) as a secondary criterion, when baseline S

is abnormal. For example, an acute rise in S

(of at least 0.5 mg/dl or 44 mol/l) to more than 4 mg/dl (350 mol/l) will serve to identify most pa- tients with ARF when their baseline S

is abnormal.

Testing a definition of acute renal failure?

The ultimate value of a definition for ARF is determined by its utility. A classification scheme for ARF should be sensitive and specific and also predictive of relevant clinical outcomes such as mortality, use of dialysis and length of hospital stay. These are testable hypotheses de- spite the lack of renal specificity for such end points [18].

It is also understood that therapy can influence the pri- mary criteria for the diagnosis of ARF. For example, vol- ume status will influence urine output and even, to some degree, S

, by altering V

. Large-dose diuretics may be used to force a urine output when it would otherwise fall into a category consistent with a diagnosis of ARF. Ulti-

mately, these cases will generally fall into defined criteria but they may cause confusion in the early acute situation.

In the end, for operative purposes, it must be assumed that patients are adequately hydrated, not treated with di- uretics except in the case of volume overload and treated with renal replacement therapy when clinically indicated.

Although this may not always be true for individuals, it should be broadly true for populations.

Conclusions

There are no perfect ways to measure renal function.

Even very precise measures of GFR will fail to distin- guish mild to moderate functional loss from normal function. Renal function reserve is important but cum- bersome to measure. Surrogate measures such as serum creatinine, while routinely available at the bedside, show limited correlation to GFR, especially in the setting of critical illness. Injury markers are being developed which might aid us in the future but are not ready for use just yet. Nonetheless, the lessons of physiology can be used to guide the development of definitions for ARF.

All the above physiological considerations have played an important role in guiding the members of the Acute Dialysis Quality Initiative (ADQI) [19] in the formula- tion of a consensus set of criteria to define ARF. These criteria are open for discussion and comments can be submitted to the ADQI website (http://www.ADQI.net).

We believe this process to be fundamental to improving our care of ARF patients and hope to move to formal testing of a final set of criteria soon.

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