Novel Biomarkers Indicating Repair or Progression After AKI
Novel Biomarkers Indicating Repair or Progression After AKI
Currently, the only consensus definition for recovery of AKI is provided by the Acute Dialysis Quality Initiative (ADQI) group. All current definitions of kidney recovery are based on functional improvement of AKI. Although complete structural reconstitution of kidney may indicate decreased chance of progression to CKD, there is no definition that incorporates structural restoration in the definition of AKI recovery.
Functional recovery of AKI is often defined as liberation from renal replacement therapy (RRT), yet fundamentally this criterion only applies to individuals with the most severe degree of AKI. Less severe stages of AKI are also associated with high morbidity and mortality, and failure to recover from these stages would greatly impact long-term outcomes. Indeed, for many, this would mean worsening of underlying CKD or de-novo CKD, with all the attendant morbidity. Therefore, definitions have emerged which incorporate absolute and relative change in serum creatinine, and outline partial or complete recovery. Some studies have defined renal recovery as an improvement in the serum creatinine concentration to within 10–20% above baseline. This definition is dependent on baseline serum creatinine availability, which is often not easily achievable. In addition, due to the nonlinear relationship between serum creatinine and glomerular filtration rate (GFR), this definition does not provide the real gained GFR given individual patients with different baseline kidney function. Another available definition for functional kidney recovery is a serum creatinine value less than 2 mg/dl. This definition is advantageous in that it ameliorates the need for baseline serum creatinine. Unfortunately, a creatinine value less than 2 mg/dl may be sub-baseline in cases of advanced CKD; therefore its utility in these individuals is limited. Also, although the achievement of a creatinine level below 2 mg/dl may signal a degree of functional recovery, it may still indicate significant deterioration in kidney function among patients with normal baseline kidney function. More importantly, arbitrary cut-offs for creatinine are not clinically meaningful. A 20-year-old black male might have a GFR of 55 ml/min/1.73 m with a creatinine of 2 mg/dl, whereas the same creatinine would equate to a GFR of 27 ml/min/1.73 m for a 70-year-old white female. To say that both have 'recovered' to the same degree would not be logical.
The ADQI group provided the first consensus definition for functional AKI recovery in 2004. The group suggested complete renal recovery is defined as a return to creatinine less than the threshold for RIFLE-R or within 50% of baseline, whereas partial renal recovery happens if patients are off RRT, but fail to return to within 50% of baseline serum creatinine. Patients who require persistent RRT (RIFLE classification L and F) are classified as nonrecovery. Although this definition gives clinicians and investigators a framework by which to approach renal recovery, it has limitations. This definition not only depends on the presence of baseline serum creatinine but also lacks clarity about the role of urine output in the recovery process. Lastly, the time and setting of AKI onset can affect a clinician's ability to apply this recovery definition.
In addition to the aforementioned limitations of each definition, all of the above criteria for functional renal recovery lack information about the time-course of the recovery process. They do not clarify how long clinicians or investigators need to follow patients to identify recovery of kidney function. On the basis of the current definition, a cut-off of 90 days following AKI is required to reach CKD status. KDIGO has proposed the concept of acute kidney disease (AKD) to address the fate of AKI before 90 days. AKD is defined as a GFR below 60 ml/min/1.73 m or evidence of structural kidney damage for less than 3 months. Although AKD allows better framing of the AKI progress, newer studies indicate that the recovery process could go on for significantly longer periods. In one study, investigators concluded that it takes the kidney at least 12–18 months to recover to a GFR of above 60 ml/min/1.73 m among adult survivors of AKI.
The above definitions do not address the repair or progression of kidney disease following AKI. The structural and anatomical changes, during recovery of kidney function, are globally ignored in all functional definitions. Following complete renal recovery, as it is defined above, serum creatinine returns close to the baseline level; however, this may not indicate that structural integrity of the kidney has been completely restored, overlooking the fact that it may have important implications on the progression of AKI to CKD that results in long-term functional changes. Animal models showed that nephron loss following AKI could result in glomerular hypertrophy of the surviving nephrons. Other structural changes following AKI could also lead to maladaptive recovery of kidney composition, which, in turn, may trigger the development of progressive CKD. These changes include adaptive repair and regeneration of the kidney functional units, systemic and intrarenal hypertension and hyperfiltration, tubular hypertrophy, tubulointerstitial fibrosis, and glomerulosclerosis. The ADQI group provided a pathway to begin building a definition of kidney injury based on both structural and functional biomarkers of AKI (Fig. 2a). One way to think about appropriate definition of renal recovery is to combine the value of functional and repair markers in the definition (Fig. 2b). The top right cell in Fig. 2b – labeled as functional recovery – refers to a condition in which structural changes persist and thus there is ongoing risk, and in which the apparent recovery may be short-lived. Also, there may be a loss of renal functional reserve that we cannot measure.
(Enlarge Image)
Figure 2.
(a) Incorporation of injury and functional markers of acute kidney injury (AKI): a new conceptual framework for acute kidney injury [21]. (b) Incorporation of recovery and functional markers of renal recovery: a new conceptual framework for renal recovery [21]. CKD, chronic kidney disease; ESRD, end-stage renal disease.
Renal Recovery Definition
Currently, the only consensus definition for recovery of AKI is provided by the Acute Dialysis Quality Initiative (ADQI) group. All current definitions of kidney recovery are based on functional improvement of AKI. Although complete structural reconstitution of kidney may indicate decreased chance of progression to CKD, there is no definition that incorporates structural restoration in the definition of AKI recovery.
Definition of Kidney Recovery
Functional recovery of AKI is often defined as liberation from renal replacement therapy (RRT), yet fundamentally this criterion only applies to individuals with the most severe degree of AKI. Less severe stages of AKI are also associated with high morbidity and mortality, and failure to recover from these stages would greatly impact long-term outcomes. Indeed, for many, this would mean worsening of underlying CKD or de-novo CKD, with all the attendant morbidity. Therefore, definitions have emerged which incorporate absolute and relative change in serum creatinine, and outline partial or complete recovery. Some studies have defined renal recovery as an improvement in the serum creatinine concentration to within 10–20% above baseline. This definition is dependent on baseline serum creatinine availability, which is often not easily achievable. In addition, due to the nonlinear relationship between serum creatinine and glomerular filtration rate (GFR), this definition does not provide the real gained GFR given individual patients with different baseline kidney function. Another available definition for functional kidney recovery is a serum creatinine value less than 2 mg/dl. This definition is advantageous in that it ameliorates the need for baseline serum creatinine. Unfortunately, a creatinine value less than 2 mg/dl may be sub-baseline in cases of advanced CKD; therefore its utility in these individuals is limited. Also, although the achievement of a creatinine level below 2 mg/dl may signal a degree of functional recovery, it may still indicate significant deterioration in kidney function among patients with normal baseline kidney function. More importantly, arbitrary cut-offs for creatinine are not clinically meaningful. A 20-year-old black male might have a GFR of 55 ml/min/1.73 m with a creatinine of 2 mg/dl, whereas the same creatinine would equate to a GFR of 27 ml/min/1.73 m for a 70-year-old white female. To say that both have 'recovered' to the same degree would not be logical.
The ADQI group provided the first consensus definition for functional AKI recovery in 2004. The group suggested complete renal recovery is defined as a return to creatinine less than the threshold for RIFLE-R or within 50% of baseline, whereas partial renal recovery happens if patients are off RRT, but fail to return to within 50% of baseline serum creatinine. Patients who require persistent RRT (RIFLE classification L and F) are classified as nonrecovery. Although this definition gives clinicians and investigators a framework by which to approach renal recovery, it has limitations. This definition not only depends on the presence of baseline serum creatinine but also lacks clarity about the role of urine output in the recovery process. Lastly, the time and setting of AKI onset can affect a clinician's ability to apply this recovery definition.
In addition to the aforementioned limitations of each definition, all of the above criteria for functional renal recovery lack information about the time-course of the recovery process. They do not clarify how long clinicians or investigators need to follow patients to identify recovery of kidney function. On the basis of the current definition, a cut-off of 90 days following AKI is required to reach CKD status. KDIGO has proposed the concept of acute kidney disease (AKD) to address the fate of AKI before 90 days. AKD is defined as a GFR below 60 ml/min/1.73 m or evidence of structural kidney damage for less than 3 months. Although AKD allows better framing of the AKI progress, newer studies indicate that the recovery process could go on for significantly longer periods. In one study, investigators concluded that it takes the kidney at least 12–18 months to recover to a GFR of above 60 ml/min/1.73 m among adult survivors of AKI.
The above definitions do not address the repair or progression of kidney disease following AKI. The structural and anatomical changes, during recovery of kidney function, are globally ignored in all functional definitions. Following complete renal recovery, as it is defined above, serum creatinine returns close to the baseline level; however, this may not indicate that structural integrity of the kidney has been completely restored, overlooking the fact that it may have important implications on the progression of AKI to CKD that results in long-term functional changes. Animal models showed that nephron loss following AKI could result in glomerular hypertrophy of the surviving nephrons. Other structural changes following AKI could also lead to maladaptive recovery of kidney composition, which, in turn, may trigger the development of progressive CKD. These changes include adaptive repair and regeneration of the kidney functional units, systemic and intrarenal hypertension and hyperfiltration, tubular hypertrophy, tubulointerstitial fibrosis, and glomerulosclerosis. The ADQI group provided a pathway to begin building a definition of kidney injury based on both structural and functional biomarkers of AKI (Fig. 2a). One way to think about appropriate definition of renal recovery is to combine the value of functional and repair markers in the definition (Fig. 2b). The top right cell in Fig. 2b – labeled as functional recovery – refers to a condition in which structural changes persist and thus there is ongoing risk, and in which the apparent recovery may be short-lived. Also, there may be a loss of renal functional reserve that we cannot measure.
(Enlarge Image)
Figure 2.
(a) Incorporation of injury and functional markers of acute kidney injury (AKI): a new conceptual framework for acute kidney injury [21]. (b) Incorporation of recovery and functional markers of renal recovery: a new conceptual framework for renal recovery [21]. CKD, chronic kidney disease; ESRD, end-stage renal disease.