Since we lack an easy, direct method of measuring renal injury, our current diagnosis of AKI relies on assaying two major renal functions and assuming that decreased functions are directly correlated with injury. Unfortunately, this may not be true, particularly early after injury.57,58
One function is the glomerular filtration rate (GFR). Even if we were able to easily and reliably measure the GFR, this would be a poor indicator of injury because, in many patients, the renal mass must be markedly reduced before the GFR decreases. An excellent example is the preserved GFR of normal people who lose half their renal mass. These normal people are living kidney donors who give one of their two kidneys to a loved one with end stage renal disease.
Furthermore, we have problems directly measuring the GFR. Instead, we rely on the serum creatinine as a surrogate. Unfortunately, it takes time (in many cases, days) for the serum creatinine to rise after renal injury. In addition, the same increment in serum creatinine may have different clinical implications depending the patient’s baseline creatinine. Furthermore, the serum creatinine level is also affected by the patient’s diet, muscle mass, and metabolic state.
The other major renal function used to diagnose renal injury is the urine output and composition (urine volume, FENa, specific gravity, etc). However, the normal kidney may produce anywhere from 0.5 liters to nearly 50 liters of urine in a 24hr period. The normal urine may be concentrated and contain almost no sodium, or be dilute and rich in sodium depending upon the patient’s physiologic state. Interpreting the quality of urine the kidney should be producing in a given patient at a given time may be a formidable challenge, and requires a detailed history and excellent serial physical exams. For example, a high FENa and low urine osmolality may be found in a patient with hypotension and oliguria, or in a person with normal renal function who has just ingested an fast-food meal with excessive sodium content. For all of these reasons, the FENa is not used as a criterion for AKI in the recent guidelines.59
An important and easily available test is the urine analysis; unfortunately it is often underutilized. If “renal failure casts” are present, the likelihood of AKI is very high.60
Unfortunately, many patients with acute renal failure will not have “renal failure casts”, and many centers lack experienced personnel to interpret the urine microscopy. Indeed, some have suggested that the severity of AKI may be predicted by quantifying the number renal failure casts.61
Needed: a renal troponin
As mentioned previously, ischemic AKI passes through the phases of pre-renal azotemia to initiation, extension, maintenance, and recovery. The diagnosis is often missed until the maintenance phase because, unlike the cardiologists, we do not have a sensitive and specific marker of early injury (e.g. a renal “troponin”). An active effort is currently underway to identify biomarkers in the blood and urine for earlier diagnosis of AKI.62
Cardiac surgery has often been used to study these markers since the time of renal insult is known.
The two broad categories of biomarkers include constitutive proteins (e.g. those that are released by dying tubule cells) and inducible markers (proteins that are upregulated following insult but are not normally expressed in tubule cells or excreted in the urine). Inducible biomarkers include neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1).63,64
Cystatin (CyC) is a constitutive protein produced by all nucleated cells that is freely filtered at the glomerulus without secretion from the tubules, and therefore the serum level serves as a functional marker of GFR. Unlike creatinine, the serum level of cystatin C is not affected by muscular mass. The α-glutathione-S-transferase (GSTs) proteins (of which there are different isotypes expressed in proximal versus distal tubules) are intracellular proteins that are released into the urinary space during tubule cell damage. Each biomarker has its individual strengths and weaknesses in accurately diagnosing AKI from different etiologies. Therefore, the most powerful clinical application of biomarkers in the diagnosis of AKI will likely be in a panel format.65
Unfortunately, assays for these biomarkers are not widely available today and most of them have not been broadly validated for clinical use. In addition, for these assays to be useful for early treatment of AKI, clinicians will need to identify patients most at risk of AKI. Unlike patients with myocardial ischemia, patients with renal ischemia are often asymptomatic. Goldstein and Chawla have proposed criteria for a “renal angina syndrome” to identify patients that should be further assessed with biomarkers in an effort to increase specificity of these tests and eventually pave the way for novel interventions.66