INTRODUCTION
Till recently there was no standard definition for acute renal failure (ARF). In 1993, the late Roger Bone penned the following words:
“Too often, the way we describe a disorder influences, and often limits, the way we think about that disorder”.
DEFINITION
The term “acute kidney injury” is intended to emphasize the reversible nature of most renal insults. ARF is a terminology now reserved for kidney injury that necessitates renal replacement therapy (RRT) (i.e. any method of conventional or intermittent dialysis).
Clinically, acute kidney injury (AKI) is characterized by a rapid reduction in kidney function resulting in failure to maintain:
- Fluid and electrolyte
- Acid–base homeostasis
- Inability to excrete nitrogenous wastes.
It is not an innocent bystander reflecting coexistent pathologies but is an independent predictor of mortality. AKI is common affecting 5–10% of hospitalized patients and up to 60% of patients admitted to the intensive care units (ICUs).
Medical understanding of AKI has been augmented by the RIFLE criteria coined by the Acute Dialysis Quality Initiative (ADQI) group in 2007. The acronym “RIFLE” classifies renal dysfunction according to the degree of impairment present: risk (R), injury (I), and failure (F), sustained loss (L) and end-stage kidney disease (E). The staging is based on the serum creatinine and the urine output criteria. If the urine output and the creatinine do not correspond to the same stage then the higher stage should be considered.
The RIFLE criteria incorporated three categories of injury and two outcomes that varied in severity. Subsequent definitions by Acute Kidney Injury Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) by 2012 eliminated the outcomes, i.e. loss and end-stage 2kidney disease (ESKD). The AKIN definition used smaller changes in serum creatinine to stage the degree of injury while the KDIGO added more definitive timelines to their criteria (Table 1).
The AKIN definition incorporated smaller changes in serum creatinine (SCr) concentration, and the KDIGO definition added more definitive time frames to the definition. A key concept for the SCr-based definitions of AKI is the identification of baseline SCr concentration. Although the initial RIFLE criteria recommended the use of an Scr concentration that would equate to estimated glomerular filtration rate (eGFR) of 75 mL/min/1.73 m2 by the Modification of Diet in Renal Disease (MDRD) study equation (MDRD-75) if no baseline was available, this definition does not account for chronic kidney disease if present. It is essential to look for a prior baseline/reference SCr concentration, ideally from the 365 days before hospital admission from a clinical context in which there was no concern for AKI (e.g. a stable clinic visit) (Table 2).
| |||||||||||||||||||||||||||||||||||||
The KDIGO–AKI definition validation was done by Rodrigues et al. 2013. It was a prospective study of 1,050 people in first 7 days after hospitalization with acute myocardial infarction (AMI). AKI defined by RIFLE in 14.8% and KDIGO 36.6% patients were associated with increased 30-day and 1-year death rate. People diagnosed as not having AKI by RIFLE, but AKI by KDIGO had increased risk of death or CKD.
MODIFICATION OF KDIGO—ADQI 16 FOR DEVELOPING COUNTRIES
Persistent AKI is characterized by the continuance of AKI by creatinine or urine output criteria (defined by KDIGO criteria) beyond 48 hours from onset. Acute kidney disease (AKD) is defined as a condition wherein AKI Stage I or greater criteria is present 7 days (or more) after an exposure. AKD that persists beyond 90 days is then considered CKD.
A Prospective Indian Study of 316 patients in 1 year evaluating the clinical profile and correlation of patients with AKI according to the KDIGO definition with respect to incidence outcome and different causes of AKI concluded that AKI is an independent risk factor for mortality in ICU. It showed that AKI is present in 37.7% of ICU patients and 9.1% patients developed AKI in ICU. The KDIGO staging could not predict outcomes because of multisystem failure.
KDIGO DEFINITION APPLICABILITY
If the urine output and the SCr do not correspond to the same stage then the higher stage should be considered.
Patients who develop AKI by KDIGO urine output criteria regardless of whether serum creatinine criteria present are at risk of developing fluid overload given the typical high obligate intake of critically ill patients.
Since creatinine lags acute changes in kidney function, the current AKI stage may not reflect current kidney function. There could be reductions in creatinine production due to acute illness, sarcopenia, and creatinine dilution during volume overload complicating evaluation of kidney function. AKI does not obey steady state kinetics for calculation of GFR.
ACUTE KIDNEY INJURY—INCIDENCE AND MORTALITY
About 25–30% of admissions to ICU are complicated by AKI, mostly as part of multiple organ dysfunction syndrome (MODS). Like acute respiratory distress syndrome it represents a syndrome rather than a single disease entity. Mortality of ARF in the ICU is 72% and non ICU-ARF is 32%. Mortality of ARF associated with acute respiratory failure is approximately 90%. Thus one must aim to prevent AKI from progressing to ARF (Fig. 1).
A special mention with regard to rhabdomyolysis in this context: It is a cause of 5–10% of ICU–ARF in a multicenter series, mostly because of trauma, muscle injury, narcotic overdose, and vascular blockade. Comorbid conditions are often present and one-third of the patients may have underlying renal disease. Early detection and aggressive renal support may improve survival by 30%4
DIAGNOSTIC STRATEGIES IN AKI (FLOWCHART 1)
- Careful history is essential
- Physical examination
- Blood investigations:
- Serum creatinine level—compare
- Complete blood count
- Newer biomarkers
- Urinalysis and urine electrolytes
- Imaging studies
- Renal biopsy.
Role of Biomarkers in Diagnosis of AKI
Serum creatinine levels have poor sensitivity and specificity in AKI, slowing recognition and its therapeutic management. Biomarkers like neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin-18, and liver-type fatty acid-binding protein (L-FABP) show promise for representing the “troponin-like” molecule of AKI. Biomarkers that reflect kidney stress like tissue injury metalloproteinase 2 (TIMP 2) and insulin-like growth factor binding protein 7 (IGFBP 7) have been recently approved by the US Food and Drug Administration for identifying patients at high risk for developing KDIGO stage 2 and 3 AKI during the next 12–24 hours. These are marketed as NephroCheck test (Astute Medical). Thus if renal injury can be diagnosed sooner in its etiologic process, therapeutic interventions can be instituted more promptly, thereby improving secondary disease prevention.
Pitfalls of Biomarkers
- Biomarkers are released at a specific time point—the rise in levels is temporary
- Cut-off levels show disparity
- Comparison with urine output and creatinine
Flowchart 1: Diagnostic strategies in acute kidney injury (AKI).
(BUN: blood urea nitrogen; ICU: intensive care unit; USG: ultrasonography)
Urinalysis and Urine Electrolytes
It is not quite fair to say that creatinine is the only biomarker of AKI. Urinalysis is a very helpful test for identifying evidence of kidney damage. Ordinarily there are very few formed elements in the urine. However, after AKI, renal epithelial cells can be shed into the tubular lumen and detected in the urine. Furthermore, these can form renal epithelial cell casts when they gel with Tamm–Horsfall protein that is present in everyone's urine. Other elements in the urinary tract can also form casts, including white blood cells that might indicate infection and red blood cells, which typically indicate glomerular inflammation (Fig. 2).
If urine dipstick is positive for blood or white cells urine should be sent for urgent microscopy for casts as well as for culture.6
Renal biopsy should be reserved for patients with suspected vasculitis or glomerulonephritis (GN), especially if a trial of steroids are considered.
Investigations should also be aimed at assessing severity, determining cause and detecting complications of AKI.
Renal ultrasound and/or a plain computed tomography of kidneys, ureters and bladder should be performed in all patients with unexplained ARF to exclude obstruction or emphysematous pyelonephritis.
ANATOMICAL CLASSIFICATION OF AKI (FIG. 3)
Once a diagnosis of AKI has been established, it is important to stratify the patient's condition by etiology (i.e. pre renal, renal, or post-renal). Stratification is important because recommended therapeutic models are tailored to these categories (Fig. 3).
General guidelines for differentiating the etiology of AKI (i.e. pre-renal vs. renal) using laboratory studies can be used (Table 3).
It is important to identify and treat the treatable factors. This involves hemodynamic resuscitation, relief of obstruction, including urinary retention, antibiotics and aggressive source control for sepsis, stopping nephrotoxic drugs where possible, decompression of abdominal compartment syndrome, and treatment of rhabdomyolysis (Table 4).
PREVENTION OF AKI
Appropriate Adequate Aggressive Volume Resuscitation
As per the Surviving Sepsis Campaign guidelines keep central venous pressure (CVP) at 8–12 mm Hg, mean arterial pressure (MAP) around 65 mm Hg, SVO2 of >70%, and maintain a urine output of 0.5–1.0 mL/kg/hr. To avoid organ edema do not over-resuscitate. Colloids or crystalloids may be equally effective but recommended is crystalloid 30 mL/kg over first 3 hours. High and medium molecular weight starches are to be avoided as they can cause osmotic nephropathy.7
Fig. 3: Anatomical classification of acute kidney injury.
(HUS: hemolytic-uremic syndrome; NSAIDs: nonsteroidal anti-inflammatory drugs)
|
| |||||||||||||||||
Vasoactive agents may be used simultaneously with volume resuscitation to restore the MAP to >65 mm Hg. Noradrenaline is the first choice to correct hypotension. Dobutamine is an inotropic agent that stimulates beta receptors and results in increased cardiac output. In theory, it can enhance tissue oxygen delivery in patients with septic shock who have received adequate fluid resuscitation and vasopressor support. In early goal-directed therapy (EGDT), dobutamine is recommended if there is evidence of tissue hypoperfusion [central venous oxygen saturation (ScvO2) < 70 mm Hg] after CVP, MAP, and hematocrit goals have been met.
Low-dose dopamine should not be used for renal protection
Dopamine has an inconsistent diuretic effect but this may cause dehydration. It does not increase creatinine clearance or prevent ARF but may cause serious toxicity problems like tachyarrhythmias, exacerbating renal, and mesenteric ischemia, impairing immune function. It should thus fundamentally not be used as an inotrope or in renal dose. Two meta-analyses of 22 trials involving 970 patients showed no benefit.
Furosemide seems to reduce juxtamedullary oxygen consumption and adds the advantage of easier maintenance of fluid and electrolyte balance by converting oliguric to nonoliguric renal failure. But it does not improve creatinine clearance or affect survival either way. It may be used but ONLY after adequate volume resuscitation. It does not prevent the development of acute tubular necrosis (ATN) and there is no reduction in mortality or need for dialysis. Furosemide is NOT a resuscitation fluid.
Nonpharmacologic Strategies for Prevention
- Minimize nephrotoxin exposure:
- Candidate agents—aminoglycosides, amphotericin B, nonsteroidal anti-inflammatory drugs (NSAIDs), and radiocontrast media
- Once daily gentamicin vs thrice daily dosing has equal efficacy but lower toxicity—5% vs 24%.
- Avoid nephrotoxic combinations: Use of NSAIDs and aminoglycoside in postoperative diabetic patients is a common clinical scenario which predisposes a patient to drug-induced AKI (Box 1).
- Adjust doses proportional to the creatinine clearance/eGFR: GFR is considered the gold standard for estimating acute or chronic renal function. GFR is almost never directly measured in the clinical setting and is almost always calculated. Current eGFR equations like Cockcroft and Gault [140-(Age × weight)/serum creatinine × 72], MDRD study, and CKD Epidemiology Collaboration (CKD-EPI), cannot be used when the creatinine concentration is not in the steady state as in AKI. In severe AKI where the patient is oligoanuric, it is assumed that the GFR would be <10 mL/min when urine output is minimal (Table 5 and Box 2).
|
RADIOCONTRAST-INDUCED NEPHROPATHY (RCIN)
It occurs in less than 1% in patients with normal renal function but increases significantly with renal insufficiency though dialysis is rarely needed for its treatment. Various risk factors can predispose to RCIN (Table 6).
Clinical Characteristics
The onset of AKI occurs 24–48 hours after exposure to contrast media. It lasts for a duration of 5–7 days. It is a nonoliguric type of AKI in majority of cases. The urinary sediment may contain the “muddy-brown” pigmented casts and renal tubular cells typical of ATN or may be quite bland. There is a low fractional excretion of sodium in this condition.
Prophylactic Strategies
- Use intravenous (IV) contrast only when necessary.
- Hydration with normal saline (1–1.5 mL/kg/hr) 6–12 hours before and after the procedure is the only treatment shown to reduce RCIN.
- Use Low or iso-osmolar (nonionic) contrast media.
- Minimize contrast volume.
- N-acetylcysteine—600–1,200 mg bid for two doses before and two doses after the procedure may be used.
| ||||||||||||||||||||
SEPSIS AND ACUTE KIDNEY INJURY
Acute kidney injury occurs in 19% of patients with sepsis, 23% with severe sepsis, and in 51% with septic shock when blood cultures are positive. The combination of AKI and sepsis is associated with a 70% mortality rate, as compared to a mortality rate of 45% among patients with AKI alone. Nitric oxide synthases, cytokines, chemokines, and adhesion molecules play a role in AKI when it is associated with sepsis. The use of early goal-directed therapy in sepsis appears to reduce mortality rates among patients with AKI as described above.
SUMMARY AND CONCLUSION
Acute kidney injury remains a ubiquitous medical condition and is associated with a high rate of mortality. Recent advances in defining and understanding AKI promise to help clinicians better diagnose and treat patients with this burdensome syndrome. Future research into the mechanisms and pathophysiology of AKI will elucidate the pathways of this complex disease process. As the clinical management of AKI remains largely supportive, the importance of primary disease prevention is clear.
ACKNOWLEDGMENTS
- Dr Valentine Lobo, Consultant Nephrologist, KEM Hospital, Pune.
- Art work: Dr Milan C Patel, Registrar IDCCM, Jehangir Hospital, Pune.
BIBLIOGRAPHY
- Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet. 2012;380:756–66.
- Bhadade R, De'Souza R, Harde MJ, et al. A prospective study of acute kidney injury according to KDIGO definition and its mortality predictors. J Assoc Physicians India. 2016;64(12):22–28.
- Dellinger R Phillip, Vincent, Jean Louis, Silva et al. Surviving sepsis in developing countries. Critical Care Med. 2008;36(8):2487–88.
- Kellum JA, Bellomo R, Ronco C. The concept of acute kidney injury and the RIFLE criteria. Contrib Nephrol. 2007;156:10–6.
- Kher V, Srisawat N. Prevention and therapy of acute kidney Injury in the developing world. Kidney Int Rep. 2017;2(4):544–58.
- Moore PK, Hsu RK, Kathleen D, et al. Management of acute kidney injury: Core Curriculum. Am J Kidney Dis. 2018;72(1):136–48.
- Rhodes Andrew, et al. Surviving, Sepsis Campaign: International Guidelines Management of Sepsis and Septic Shock. Critical care Medicine. 2017;45(3):486–522.
- Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute kidney injury: A systematic review. Kidney Int. 2008 Mar;73(5):538–46.
- Rodrigues FB, Bruetto RG, Torres US, et al. Incidence and mortality of acute kidney injury after myocardial infarction: a comparison between KDIGO and RIFLE criteria. PLoS One. 2013: 23;8(7):e69998.