Tubuli and interstitium
Nephrotoxins
• Contrast
• Medications
• Hemolysis
• Rhabdomyolysis
• Myeloma
Allergic reaction
• NSAID
• Antibiotics
• Proton pump inhibitors
• 5-ASA
Ischemia
Sepsis
Local infection
Tumor lysis syndrome
Glomerulus
Inflammatory systemic disease involving kidney
• Systemic lupus erythematosis
• Systemic vasculitis
Primary glomerulonephritis
Infections with secondary glomerulonephritis
• Hepatitis B
• Hepatitis C
• HIV
Vessel
Atheroembolic renal disease
Renal vein thrombosis
Thrombotic microangiopathy
Antiphospholipid syndrome
Acute tubular necrosis (ATN) is the most common histopathological change among various pathogenesis of renal AKI. Nephrotoxins, renal ischemia, and sepsis are three major causes of ATN [14–16]. A number of drugs and exogenous and endogenous toxins can cause ATN. These include aminoglycosides, heme pigments, cisplatin, radiocontrast media, pentamidine, foscarnet, cidofovir, tenofovir, intravenous immunoglobulin, mannitol, hydroxyethyl starch, and synthetic cannabinoids. All causes of severe prerenal AKI, particularly if accompanied by hypotension, surgery, and/or sepsis, can lead to ischemic ATN. Sepsis-induced ATN is often associated with prerenal factors such as reduced renal perfusion and systemic hypotension, and other factors, including cytokine release and neutrophil activation by cytokines, can also contribute.
Among all causes of renal AKI, drugs, contrast, cardiac surgery, and sepsis are relatively common. AKI-related drugs include NSAIDs, several antimicrobial agents, and several chemotherapeutic drugs [17]. The incidence of contrast-induced AKI following coronary angiography is about 2.6–13% [18]. Although noncardiac surgery is deemed to be related to AKI at a lower risk than cardiac surgery [19], one study showed that 7% developed AKI which was defined as a >50% increase in SCr levels after noncardiac surgery [20]. The incidence of AKI in patients undergoing cardiac surgery ranged from 1 to 50%, relying on the classification of AKI and the type of surgery [21]. AKI is common in patients with sepsis, while hospital mortality in septic shock patients with AKI has almost doubled [22].
7.2.4 Risk Factors for AKI
Some patient-specific factors, including old age, diabetes, left ventricular systolic dysfunction, dehydration, and CKD, may predispose the patient to develop AKI when exposed to the etiology of AKI [2, 23]. Besides these high risk factors, several conditions that may occur during some particular operations are related to the development of AKI. For patients who need intra-aortic balloon counterpulsation, who need to use cardiopulmonary machines for too long, or who need blood transfusion to supplement blood volume, the risk of developing AKI is significantly increased [24]. When patients with CKD encounter with any cause of AKI, they are prone to progress to a more serious AKI requiring RRT, and they are also more likely to deteriorate to end-stage renal disease (ESRD) [25].
For preventing the development of AKI, especially in patients with CKD, estimating and identifying patients who may be at high risk before exposure to potential nephrotoxic drugs or other nephrotoxins or before surgery is of great importance.
7.3 Bidirectional Relationship Between AKI and CKD
7.3.1 Effect of CKD on Development or Outcome of AKI
7.3.1.1 CKD Is a Potent Risk Factor for AKI
It can be predicted that the decrease of renal mass and nephron number, vascular insufficiency, and reduced tissue repair ability in patients with CKD may decrease the renal homeostasis under the action of acute stressor, thus making this population more vulnerable to the influence of AKI. Almost all AKI risk prediction scores have confirmed that CKD is one of the strongest risk factors for AKI, which has been proved in many large retrospective cohort studies.
The proportion of preexisting CKD has been 30–35% in most studies on AKI in hospitalized patients [10, 26–29] but as high as 75% in one large series [15]. An analysis showed that the risk of developing dialysis-requiring AKI increased from twofold in patients with CKD whose baseline estimated GFR (eGFR) was in stage 3a to 40-fold in those with CKD whose baseline eGFR was in stage 5 when compared with the risk in control patients with baseline eGFR ≥60 mL/min/1.73 m2, which suggested that CKD is a potent predictor of dialysis-requiring AKI in hospitalized patients [15]. This study was also the first to report that proteinuria is a strong risk factor for AKI [15]. Another analysis of data from a CKD cohort with an eGFR <30 mL/min/1.73m2 showed that, within a median 19-month follow-up, 44.9% of patients had, at least once, an episode of AKI which is defined as a 25% decrease in eGFR over a period of 25 days [30]. The relationship between baseline renal function and the occurrence of AKI was assessed in one study and the findings displayed that patients with eGFR <30 mL/min/1.73m2 were 18 times more likely to develop AKI than those with eGFR >60 mL/min/1.73 m2, which suggested that the incidence of AKI evidently increased following the decline of baseline eGFR [31].
7.3.1.2 CKD Worsens Renal Outcome After AKI
Some studies have shown that AKI-related attributional mortality is higher in patients with CKD than in those with normal renal function. Actually, not only does the risk of AKI increase significantly in patients with CKD, but the existence of CKD does alter or, rather, increase the correlation between AKI and its adverse outcomes. Observational studies have also found that renal function in patients with CKD after an episode of dialysis-requiring AKI is less likely to return to baseline levels than that in those without CKD [1].
A study enrolled 48 patients initiating dialysis for AKI showed that the survivors with preexisting CKD were more likely to be dialysis-dependent at 90 days (50% vs. 11% of those without preexisting CKD) [16]. Similar findings were noted in a review of 299 critically ill patients with dialysis-requiring AKI, 102 of whom had underlying CKD. Among survivors, the rate of dialysis dependence at hospital discharge was higher in those with underlying CKD (34%) than in those without CKD (5%) [29]. A stratified analysis of postdischarge outcomes of inpatients with medical insurance showed that AKI patients with prior CKD had a 41-fold increased risk of developing ESRD, while patients with AKI alone had a 13-fold increased risk of progression to ESRD [32]. Another analysis displayed that individuals with a baseline eGFR <30 mL/min/1.73 m2 and severe AKI had a 4.71-fold increase in the risk of long-term outcome of ESRD or death, which suggested that there is a consistent and graded relationship between both baseline eGFR and severity of AKI and long-term adverse outcomes [31].
7.3.2 Effect of AKI on Onset or Progression of CKD
Numerous studies have linked AKI to occurrence and progression of CKD. Indeed, in AKI survivors, the duration, severity, and recovery of AKI are related to the subsequent development of de novo CKD or deterioration of underlying CKD, and a growing body of evidence have confirmed the influence of AKI on CKD. Furthermore, patients with CKD who develop AKI are more likely to progress to ESRD than those who never have an AKI episode. The KDIGO clinical practice guideline on AKI recommended the evaluation of patients by clinicians at 3 months after AKI for resolution, new onset, or worsening of preexisting CKD [3].
7.3.2.1 AKI Increases the Risk of Both De Novo CKD and Deterioration of Underlying CKD
A population-based matched cohort study that included 3769 patients with dialysis-requiring AKI who survived free of dialysis for at least 30 days after discharge reported a 3.2-fold increase in the risk of incidence of chronic dialysis [33]. An analysis of matched data obtained from US Medicare beneficiary claims and the US Renal Data System showed that patients aged 67 years or older who developed AKI were 6.7 times more likely to develop ESRD at 2 years after discharge than those without AKI. Patients with a history of CKD who developed AKI had a 41-fold increase in the risk of ESRD [32]. In an analysis that compared 36,980 patients admitted to a US Department of Veterans Affairs facility between 1999 and 2005 with patients admitted with myocardial infarction (MI) alone, those admitted with AKI or AKI plus MI had a 2.07-fold or 2.30-fold increase in the risk of having an adverse kidney outcome (defined as a >25% decline in eGFR, need for long-term dialysis, or death) at a maximum of 6 years of follow-up, respectively [34]. A meta-analysis that included 13 cohort studies showed an 8.8-fold and 3.1-fold increase in the risk of developing CKD and ESRD in patients who developed AKI than in those who did not, respectively [35].
Several reports suggest that an episode of AKI is related to an elevated hazard for CKD even among patients without any detectable kidney disease. For example, 1610 patients enrolled in a cohort study developed AKI during hospitalization and their kidney functions were normal before AKI. Their kidney functions recovered to at least 90% of the baseline levels within 3 months after the onset of AKI, and in 81% of these patients, the kidney function recovered to pre-AKI levels within 4 days. However, compared with matched control patients who didn’t develop AKI, patients were more prone to develop CKD at 3.3 years after the episode of AKI [36]. In another cohort study, 3809 patients with AKI and normal pre-AKI kidney function were observed, and it was found that AKI had a correlation with a high risk of CKD at 2.5 years in these patients [37].
7.3.2.2 Factors Affecting Effect of AKI on Onset or Progression of CKD
Effect of AKI severity on onset or progression of CKD
In a population-based cohort study, patients who developed reversible AKI, i.e., whose renal function recovered to more than 75% of baseline, had better clinical outcomes than those with irreversible AKI. Compared to patients with reversible AKI, the irreversible group had a 1.26-fold increase in the risk of death and a 4.13-fold increase in the risk of composite renal outcomes which included doubling of SCr level and ESRD [38].
Several studies linked dialysis-requiring AKI to progression of CKD. Dialysis-requiring AKI means that AKI is so severe that RRT is indispensable, and the “dialysis” in this phrase refers to various acute RRT modalities, e.g., continuous RRT, peritoneal dialysis, or intermittent hemodialysis. In an analysis of information from a large integrated healthcare delivery system concerning patients with baseline eGFR ≥45 mL/min/1.73 m2 who underwent an episode of dialysis-requiring AKI and recovered to be released from RRT at one month after hospital discharge, an association between a 28-fold higher risk of deteriorating stage 4 or 5 CKD and the previous dialysis-requiring AKI was observed [14]. Another analysis of data from the same system showed a 47% higher risk of ESRD in the following 30 days after discharge in patients with underlying CKD (baseline eGFR <45 mL/min/1.73 m2) who went through dialysis-requiring AKI, comparing to CKD patients with same level of baseline eGFR who did not have AKI [41].
In one study enrolled in children with AKI in ICU who developed subsequent CKD that was defined as albuminuria or eGFR <60 mL/min/1.73 m2, incidence of CKD elevated from 5% in patients with AKIN stage 1 AKI (defined as an increase in SCr concentration by ≥50% or by ≥0.3 mg/dL from baseline) to 17% in patients with stage 3 AKI (defined as a ≥3-fold increase in SCr concentration from baseline, an increase in SCr concentration to ≥4 mg/dL with an absolute increase by 0.5 mg/dL, or requirement for RRT) in the following 1–3 years after AKI. It suggested that an increase of CKD incidence was closely related to the grading of previous AKI [49].
An analysis of data from the Department of Veterans Affairs healthcare system presented that the increase in the severity of AKI at each stage (based on the RIFLE criteria) was associated with a 4.4-fold increase in odds ratio of progressing stage 4 or 5 CKD. In addition, dialysis-requiring AKI alone was related to a 53-fold increase in odds ratio of progressing stage 4 or 5 CKD. These results demonstrated that the severity of AKI could be used as a risk stratification factor for CKD progression [50].
Cumulative effect of repeated AKI episodes on progression of CKD
According to a study focusing on recurrent AKI which was defined as one episode of AKI happened again in the following 12 months after a previous AKI, the prevalence rate of recurrent AKI was 25% [44]. Although most studies paid more attention to the consequence of one episode of AKI for the risk of CKD, the effects of multiple episodes of AKI on the progression of CKD were analyzed in patients with diabetes mellitus from the US Department of Veterans Affairs healthcare system. The findings showed a 3.6-fold increase in the risk of stage 4 CKD in patients with one episode of AKI, compared to patients without AKI. In addition, for every additional episode of AKI, this risk increased by an extra double [43]. These observations further increase the likelihood of the phenomenon observed in other studies, that is, repeated episodes of AKI promote the progression of CKD, which is characterized by a no-linear decline in kidney function [45–48]. Nowadays, it has been generally accepted that the progression of CKD isn’t at a constant rate with a nonlinear trajectory of decline in eGFR.
Reversible AKI is associated with a risk of developing CKD
An analysis of data from a large integrated healthcare delivery system in Central Pennsylvania suggested that an increase in the risk of subsequent CKD development was even correlation with reversible AKI, which was defined as that the increase in SCr levels fall back to within no more than 10% of baseline values in the following 3 months after AKI in patients without CKD at baseline. The incidence of CKD in the patients who suffered from reversible AKI was 1.9-fold higher than that in matched controls who did not experience AKI [51]. In another study, data from a large integrated healthcare delivery system in Utah was analyzed and it was found that AKI with almost complete renal function recovery which was defined as that the return of SCr values is less than 1.1 times of the baseline values was significantly related to the incident of stage 3 CKD. At a median follow-up of 30 months, the incidence of CKD was 15% in individuals with recovery AKI, showing a 3.8-fold increase in the risk of CKD development compared to the risk in individuals who did not experience AKI [37]. The analysis of Veterans Health Administration data revealed that even the individual experienced stage 1 AKI according to KDIGO criteria with quick recovery which was defined as the return of SCr levels from peak to no more than 0.3 mg/dL above baseline values within 48 h had a 1.4-fold increase in the risk of CKD development [52].
CKD is one of possible factors leading to irreversible AKI
Several studies suggested that the decline of renal function owing to AKI was more possible to be irreversible in patients with lower baseline GFR, old age, heart failure, hypertension, or hypoalbuminemia [36, 39]. An analysis of data from 281 patients who developed in-hospital dialysis-requiring AKI and continued outpatient dialysis after discharge showed that renal function returned at a median of 8 months in 52 (19%) patients, in which most (94%) exhibited recovery within 6 months. The findings suggested that ATN secondary to surgery or sepsis and higher level of baseline eGFR were two independent factors for predicting recovery of renal function while heart failure independently predicted no recovery within 6 months after AKI. The first RRT in ICU and catheter access for dialysis were not independent predictors. Even with a higher level of baseline eGFR, the decline of renal function in patients with heart failure who developed AKI was more prone to be irreversible [40].
Proteinuria aggravates the effect of AKI on the progression of CKD
In addition to eGFR, proteinuria is also an important parameter reflecting the severity of CKD. The relationship between baseline eGFR, proteinuria, and AKI was studied in a large database of nearly one million adults in Alberta, Canada. The results of observation showed that a higher risk of AKI was correlated with the lower levels of baseline eGFR and the higher levels of urinary protein excretion, and the further analysis revealed that massive proteinuria could serve as a predictor for long-term prognosis of kidney, e.g., doubling of SCr levels or ESRD, after an AKI episode. These studies confirmed that the effects of an AKI episode on the long-term decline in kidney function at all levels of baseline eGFR can be aggravated by proteinuria [42].
7.4 AKI on CKD (Also Applicable to AKI Alone)
7.4.1 Diagnosis
As mentioned above, AKI is a powerful accelerator to push forward the progression of CKD. For patients with CKD, it is important to make a diagnosis in time when AKI occurs. When AKI occurs, however, patients rarely develop symptoms and signs owing to AKI, and symptoms and signs are more likely to be related to underlying causes than AKI itself. Therefore, examination and treatment should depend on the clinical background and underlying causes (see “common causes of AKI” in this chapter). In addition to the condition of CKD, other medical histories, including exposure to nephrotoxic drugs and other nephrotoxins, should be reviewed in detail. Obstruction of any part of the urinary tract should be excluded initially. Ultrasound should be performed to examine the size of bilateral kidneys, and the length of kidneys <8 cm may indicate CKD rather than AKI, but does not rule out AKI-on-CKD [11].
Blood samples should be collected for analyzing SCr, electrolytes, standard bicarbonate, blood cell count, and serum albumin. Dipstick urine analysis and analysis of urine sediment should be used routinely to investigate the AKI causes. Urine volume should be regularly measured as oliguria and anuria is common in patients with AKI, and urine volume is an earlier marker of the progression in AKI than level of SCr [2]. For patients with CKD, the diagnosis of AKI complies with the KDIGO criteria. Meanwhile, determination of the cause of AKI is essential. The activity or rapid progression of the primary cause of CKD should also be taken into account.
7.4.1.1 Differential Diagnosis Between Prerenal and Renal AKI
- 1.
Urinalysis.
- 2.
Fractional excretion of sodium and, to a lesser degree, urinary sodium concentration. The fractional excretion of urea may be helpful in patients being treated with diuretics.
- 3.
Response to fluid repletion in patients with evidence of volume depletion, which is the gold standard for the diagnosis of prerenal disease. This does not apply to prerenal disease due to heart failure (cardiorenal syndrome) or cirrhosis (hepatorenal syndrome).
Other parameters that may be helpful in selected patients include the following: blood urea nitrogen/SCr ratio, rate of increase in SCr concentration, urine osmolality, and urine volume.
In patients with prerenal AKI due to cardiorenal syndrome or abdominal compartment syndrome, definitive diagnosis should be established through cardiac functional evaluation (e.g., echocardiography, invasive hemodynamic monitoring) or bladder pressure transduction, respectively.
7.4.1.2 Concurrent of Prerenal and Renal AKI
Prerenal and renal AKI often overlap in many patients. Concomitant prerenal and renal AKI may occur in patients with rhabdomyolysis, hypercalcemia, or sepsis, and may also be observed in patients after cardiac surgery. Rhabdomyolysis is usually related to hypovolemia which may result in prerenal AKI, meanwhile, myoglobin and heme proteins may induce intraluminal cast formation and tubular obstruction, which is the direct toxic effects on the kidney. Hypercalcemia is also a disorder which may cause both prerenal and renal AKI owing to the severe hypovolemia and the simultaneously nephrotoxicity of calcium [53]. The causes of AKI in sepsis are multifactorial, which include hypotension, activation of sympathetic nerves system, and mediating effects of hormones and inflammatory factors [54]. The causes of AKI after cardiac surgery are usually ischemia, hypotension, embolism, inflammation, and free hemoglobin in blood transfusions.
7.4.2 Biomarkers of Kidney Injury
It is assumed that delayed detection of AKI is one of the reasons for the failure of intervention trials designed to treat AKI. Hence, kidney injury biomarkers for early detection of the clinical process of AKI and for predicting the need of dialysis or other complications before the changes of the functional biomarkers (i.e., SCr) have been searching by a lot of efforts. These biomarkers including kidney injury molecule 1 (KIM-1), neutrophil gelatinase associated lipocalin (NGAL), liver-type fatty acid-binding protein (l-FABP), interleukin 18 (IL-18), insulin-like growth factor binding protein 7 (IGFBP-7), and tissue inhibitor of metalloproteinase-2 (TIMP-2) can provide information about tubular damage, usually before renal function declines.
l-FABP—After ischemic injury, the expression of l-FABP was induced in renal proximal tubules. One hour after injury, the amount of this protein in urine increases to detectable levels, reaching a peak 6 h after AKI [55].
NGAL—An enzyme that can activate protective enzymes and prevent production of oxygen-free radicals is released from damaged proximal and distal tubular cells after kidney injury. The neutrophils and liver cells in septic patients also release this enzyme. It can be detected in urine and serum 3 h after AKI, reaching a peak 6 h after AKI [56].
IL-18—A pro-inflammatory cytokine that is upregulated in proximal tubule after ischemic AKI. It is detectable in urine and serum 6 h after AKI and peaks 12–18 h after AKI [57].
IGFBP-7 and TIMP-2—Both proteins can induce G1 cell cycle arrest in G1 phase, thus preventing endothelial cells proliferation. They are detectable in urine 12 h after AKI [58].
KIM-1—A protein produced by proximal tubular cells after injury can activate immune cells resulting in elimination and reconstructing of damaged tubule. It is detectable in urine 12–24 h after AKI and peaks 48–72 h after AKI [59].
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