|
 
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| REVIEW ARTICLE |
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| Year : 2019 | Volume
: 1
| Issue : 1 | Page : 35-41 |
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The Short- and Long-Term Burden of Acute Kidney Injury
Jonah G Powell-Tuck1, Jorge Cerda2, Marlies Ostermann1
1 Department of Critical Care, King's College London, Guy's and St Thomas' Hospitals, London, UK
2 Department of Medicine, Division of Nephrology, Albany Medical College, Albany, NY, USA
| Date of Web Publication | 4-Jan-2019 |
Correspondence Address:
Dr. Marlies Ostermann
Department of Critical Care, King's College London, Guy's and St Thomas' NHS Foundation Hospital, London SE1 7EH
UK
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jtccm.jtccm_7_18
Acute kidney injury (AKI) is a common complication of acute illness and carries a significant risk of mortality and morbidity, resulting in high health-care-associated costs. The incidence of AKI appears to be rising, making it ever more important to understand its acute and chronic consequences. In this review, we explore the evolving epidemiology of AKI, describe the impact of AKI on other organs, and discuss the short- and long-term effects of AKI on mortality and morbidity and its economic burden.
Keywords: Acute kidney injury, economics, mortality, outcomes
How to cite this article:
Powell-Tuck JG, Cerda J, Ostermann M. The Short- and Long-Term Burden of Acute Kidney Injury. J Transl Crit Care Med 2019;1:35-41 |
| Introduction | |  |
Acute kidney injury (AKI) is a common complication of acute illness and carries a significant risk of mortality and morbidity. The incidence of AKI appears to be rising, making it ever more important to understand its acute and chronic consequences. In this review, we explore the short- and long-term burden of AKI.
| Definition and Pathophysiology | | |
AKI is characterized by a sudden deterioration in kidney function resulting in failure of its excretory and homeostatic processes. Based on the most recent Kidney Disease Improving Global Outcomes consensus document,[1] AKI is defined by a rise in serum creatinine and/or fall in urine output. Depending on the degree of creatinine rise and oliguria, it is divided into three stages of severity [Table 1]. While AKI is defined and graded by failure of excretory function, the role of the kidney is much broader than this. As such, kidney failure has wider consequences than those linked directly to failure of filtration.
AKI is a syndrome, encompassing a broad spectrum of etiologies and varied and complex pathophysiologies. Several causative processes have been implicated including endothelial injury, dysregulation of the microcirculation, tubular cell injury, leukocyte infiltration with release of cytokines, and activation of the local coagulation system.[2] These pathophysiological processes may occur sequentially as well as simultaneously.
| Epidemiology | | |
Worldwide, the incidence of AKI is rising.[3],[4] This appears to be, at least in part, due to aging populations and an increasing prevalence of both diabetes and chronic kidney disease (CKD), all of which have been shown to increase the risk of AKI.[5]
In a large systematic review including over 49 million patients, the worldwide incidence of AKI during hospital admission was 20%.[6] Among patients admitted to the Intensive Care Unit (ICU), more than 50% are reported to develop AKI within the 1st week of critical care therapy.[7] A large Italian study found that 65% of critical care patients had developed AKI by the end of their critical care stay.[8]
There are multiple factors that contribute to the increased risk of AKI. A review of the United States hospital discharges found that AKI was more common in elderly patients, male patients and those whose ethnicity was referred to as Black, with patients more commonly being diagnosed when having underlying cancer, CKD, chronic heart failure, chronic respiratory failure, human immunodeficiency virus, or cancer.[9] Other predisposing risk factors include chronic comorbidities such as diabetes, vascular disease, hypertension, and chronic liver disease. Potentially modifiable risk factors are fluid overload, sepsis, trauma, cardiac surgery, and exposure to radiocontrast media or nephrotoxic drugs.[5]
| Short-Term Sequelae | | |
The direct consequences of disruption of the kidneys' usual homeostatic functions are usually clear to appreciate. However, it is increasingly recognized that kidney failure has a greater impact on the body than previously thought. While it can be difficult to establish what is cause and effect, there is increasing evidence that kidney failure leads to distant organ dysfunction and high health-care costs [Figure 1].
Direct effects of acute kidney injury
As kidney function deteriorates, there are a number of clear direct consequences which include electrolyte and acid–base disturbances, uremia, disruption of endocrine feedback mechanisms, altered drug metabolism, and fluid overload.
- Electrolyte imbalances, particularly when severe, can lead to cardiac arrhythmias and myocardial depression, which may be exacerbated further by uremia and acidosis and the inflammatory processes explained below[10]
- Fluid accumulation is common as a result of impaired excretion and activation of the renin–aldosterone system
- Uremia is associated with increased permeability and inflammation of serous membranes leading to pericarditis, pleurisy, and gastroduodenitis. Associated platelet dysfunction may increase the risk of bleeding. Uremia and increased permeability of the blood–brain barrier may also be responsible for some of the neurological symptoms of AKI, including lethargy and confusion
- An increasingly acidotic environment can lead to cardiac instability and may also decrease hepatic blood flow.[11] In addition, the reduction in pH in the cerebrospinal fluid can cause vasodilation of cerebral parenchymal arterioles resulting in increased risk of cerebral edema[12]
- Reduced renal clearance will clearly affect metabolism of medications and toxins that are excreted by the kidneys. Pharmacokinetics may also be altered.[13]
Organ crosstalk
Increasingly, it is being recognized that AKI results in distant organ dysfunction beyond the effects of fluid and electrolyte imbalances [Table 2]. Animal model evidence suggests that AKI is associated with elevated inflammatory mediators which contribute to intrarenal and systemic inflammation, endothelial dysfunction, and nonrenal organ failure. The exact causes of this pro-inflammatory state are debated. Activation of intrarenal inflammatory cells, reduced cytokine clearance, and nephron cell damage are potential explanations.[11] | Table 2: Potential mechanisms for organ dysfunction in Acute Kidney Injury
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Within the lungs, neutrophils are found to accumulate within 1–2 h of AKI, with higher levels of plasminogen activator inhibitor 1, interleukin (IL)-6, and tumor necrosis factor (TNF) found in the bloodstream and lung tissue.[14],[15] Experiments have shown that renal injury can lead to increased vascular permeability and dysregulation of salt and water transport, two important contributors to the development of acute lung injury.[16]
Similarly, the heart may also be affected by these inflammatory processes. Circulating cytokines released during AKI have been found to have direct cardioinhibitory effects resulting in decreased cardiac contractility.[10] Rodent models exposed to bilateral renal ischemic injury had increased levels of IL-1, anti-TNF, and cardiac myeloperoxidase within the myocardium resulting in myocyte apoptosis and reduced cardiac contractility.[17]
AKI-induced pro-inflammatory endothelial changes have also been noted in both the liver and brain. Within the liver, AKI is associated with neutrophil infiltration and oxidative stress with increased vascular permeability and activation of inflammatory pathways. Within the brain, endothelial dysfunction can lead to disruption of the blood–brain barrier facilitating an influx of inflammatory and osmotic agents into the brain. This in addition to cytokine-related activation of microglial cells and disruption of aquaporins may contribute to cerebral edema.[15],[18]
AKI predisposes to sepsis. Work from the PICARD study group showed that 40% of patients with AKI developed sepsis 5 days following the initial insult.[19] Similar results were seen in a large Taiwanese study which demonstrated that after multivariable adjustment, patients with AKI requiring dialysis were at a higher risk than patients without AKI for developing de novo severe sepsis (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71–2.31; P < 0.001).[20]
Inpatient mortality and length of stay
Unsurprisingly, those with AKI have an increased length of stay (LOS) in hospital. In the US, AKI is associated with an average increase in length of hospital stay of 3.5 days,[21] while a UK study found that compared to those with no AKI, LOS was 1.5-, 1.9-, and 2.2-fold greater in those with AKI Stages I, II, and III, respectively.[22]
AKI is a known independent risk factor for inpatient mortality.[2] In a review of 330,000 hospital discharges in the US, hospital mortality of patients with AKI was 21.3% compared to 2.3% in those without AKI (P < 0.0001).[9] Similarly, an Australian study concluded that the presence of AKI increased the chance of death with an odds ratio of 3.29.[23] Mortality rates increase with higher severity of AKI with the odds of dying rising from 1.68 for a critical care admission with AKI Stage 1 to 2.94 for AKI Stage 2 and 6.88 for AKI Stage 3 when compared with those with no kidney injury.[7] Indeed, even those who do not require dialysis or who had very small rises in serum creatinine have been found to have an increased risk of mortality.[12],[24]
| Long-Term Sequelae | | |
Long-term mortality
AKI survivors continue to have an increased risk of premature mortality long after renal recovery and hospital discharge. The reasons are multifactorial and may be due to preexisting comorbidities that also predisposed to AKI. However, even when correcting for these risk factors, AKI is independently associated with premature mortality. A study which looked at patients who were alive 90 days following hospital discharge and followed them over a 4-year period found that AKI was associated with a 41% increase in mortality (adjusted HR 1.41; 95% CI: 1.39–1.43). The risk of death increased with severity of AKI with adjusted HRs 1.39, 1.51, and 1.71 for AKI Stages I, II, and III, respectively, compared with no AKI.[25]
The mortality of those admitted to critical care with severe AKI requiring dialysis appears worse. A single-center study reported mortality at discharge in this cohort of patients to be 59.7% which increased to 72.1% at 3 years.[21] Other studies report similar mortality rates at 5 years.[26] A subanalysis of the RENAL study, a renal replacement therapy (RRT) dosing trial, showed a mortality rate of 62% at 3.5 years following randomization in those who survived the first 90 days.[27]
Acute on CKD (AoCKD) disease carries a particularly poor prognosis. According to data from the U.S. hospitals, the mortality following AoCKD at 6 months is 63% compared to 50% for AKI without CKD.[28]
Risk of readmission to the hospital is also increased in patients with AKI. Rates of rehospitalization were greater in those with AKI during admission than the control group (44.93 person-years vs. 37.18/100 person-years, adjusted HR: 1.21; 95% CI: 1.18–1.24)[12] in a single-center study of patients with AKI who did not require RRT.
Renal outcome
There is evidence that AKI is an independent risk factor for CKD and end-stage renal failure (ESRF). Even patients with AKI in whom creatinine levels return to baseline remain at risk of further episodes of AKI and progression to CKD. About 31% of patients in a surgical cohort with AKI developed at least one further episode of AKI within 12 months which was associated with worse mortality.[29]
Reported incidences of nonrecovery of renal function after AKI vary mainly due to differences in criteria and patient characteristics.[5] A group that followed patients who survived an episode of dialysis-requiring AKI found that at 5 years, 14% of the surviving patients had CKD, while 5% developed ESRF and needed long-term dialysis.[26] The results from this single-center study match the findings of the RENAL study which showed that 5.4% of AKI survivors required chronic dialysis at 3.5 years.[27] Importantly, normalization of creatinine following an episode of AKI does not equate to full recovery of kidney function. Persistent proteinuria over a number of years has been documented in more than 40% of AKI Stage III survivors.[27]
The exact mechanisms that influence repair and kidney recovery after AKI remain debated. Important contributors to the progression to CKD from AKI include cell cycle arrest, glomerular hyperfiltration and intrarenal hypertension, maladaptive tubular repair, a reduction in the number of peritubular capillaries, and increased deposition of collagen.[2]
While AKI is a risk factor for CKD, CKD is also a risk factor for AKI, and AoCKD is an even stronger risk factor for ESRF. Ishani et al.[30] found that in hospitalized patients older than 67 years, AKI was associated with a nearly 7-fold increase in the development of ESRF during the following 2 years in comparison with patients who did not develop AKI. AoCKD was associated with a 41-fold increase in the development of ESRF, de novo AKI with a 13-fold increase, and CKD in the absence of AKI with a nearly 8.5-fold increase in comparison with patients without AKI or CKD.
Other adverse effects
The long-term consequences of AKI extend beyond increases in mortality and deterioration in kidney function [Table 3]. Demonstrated associations include an increased risk of cardiovascular events including myocardial infarctions and strokes.[27],[31] In two large studies of over 4000 patients who had recovered from AKI, the incidence of coronary events was 19.8 versus 10.3/1,000 person-years in the non-AKI group (HR: 1.67; 95% CI: 1.36–2.04)[31] while the incidence and severity of stroke were also higher in the AKI group.[32] Both of these factors were independent of subsequent progression to CKD and of diabetes.
Following an episode of AKI, patients also appear to be at higher risk of bone fractures. Wang et al. demonstrated that patients who had survived an episode of AKI requiring dialysis were at increased risk of fractures, regardless of progression to CKD.[22] It is not clear whether this is a result of bone remodeling at the time of the AKI leading to bone weakness or whether persisting bone demineralization occurs following AKI.
AKI also appears to have a lasting impact on patients' functional status. A recent US study looked at the association between frailty and AKI. In survivors of ICU admissions with either respiratory failure or shock, they discovered that worsening severity of AKI was associated with worsening clinical frailty status at 3 and 12 months following discharge.[33]
| Economics of Acute Kidney Injury | | |
AKI has a major impact on health-care costs. Using both routine national data for the National Health Service (NHS) in England and laboratory data from a district general hospital in South England, Kerr et al.[34] estimated the annual cost of AKI-related inpatient care in England at £1.02 billion, just over 1% of the NHS budget. The lifetime cost of postdischarge care for people who had AKI during hospital admission in 2010–2011 in the UK was estimated at £179 million. Similar data from the UK shows that severe AKI Stage 3 had a particularly high-economic impact when compared with AKI Stages 1 and 2.[35] Importantly, the costs related to inpatient AKI may be even higher since up to four-fifths of cases may not be captured in routine hospital data.
In a recent study involving 239,906 hospitalized subjects in Alberta, Canada, Collister et al. measured health-care utilization and costs from inpatient, outpatient, and physician claims datasets to estimate AKI-associated costs.[36] Their results demonstrated that greater severity of AKI was associated with incremental increases in LOS (2.8 vs. 7.4 days) and costs ($3779–$18,291 Canadian dollars) from admission to recovery to 3 months. Beyond 3 months and up to 12 months postadmission, AKI recovery was associated with incremental costs of $2912–$3231 and $6035–$8563 Canadian dollars, respectively. In Canada, the estimated incremental cost of AKI is estimated to be over $200 million Canadian dollars/year. Importantly, although the incremental cost per patient was much greater for those with more severe AKI, especially in those requiring dialysis, even the mildest form of AKI resulted in adjusted costs at 12 months that were 1.2–1.3 times higher than those for patients without AKI.
A recent US survey showed that AKI is the most common reason for inhospital nephrology consultation and represents a major public health issue.[37] Three measurable outcomes regarding the effects of AKI include LOS, progression to CKD or ESRF, and mortality.[38] Approximately 300,000 people die in the US annually with AKI and 1.2 million people develop AKI during a hospital stay, resulting in an average 3.5-day increase in LOS. Each one of those consequences is associated with dramatically increased patient care costs.[21] In the US, it has been estimated that an average AKI cost increase of $7500/admission results in national increase in hospital costs close to USD 9 billion/year.[24]
Data from Massachusetts hospitals over 2 years demonstrated that AKI results in 8% higher mortality and higher hospital resource utilization. When comparing admissions with an AKI versus those without AKI median direct hospital costs increased by $2600 whilst length of stay increased by 5 days.[39] Chertow et al. showed that even uncomplicated AKI was associated with greater hospital costs and LOS.[24],[40] For example, an increase in serum creatinine of 0.5 mg/dL (44 μmol/L) was associated with a 6.5-fold (95% CI 5.0–8.5) increase in the odds of death, a 3.5-day increase in LOS, and nearly $7500 in excess hospital costs.[21]
Many of those patients who develop inhospital AKI have underlying CKD, which is in itself a significant factor in cost increase. In univariate analysis, the average total inhospital costs increased with each stage of CKD (€2926; €3466; €4208; P < 0.0001).[41] Treating patients with CKD Stages 4 and 5 utilized markedly more resources than patients with ST-elevation myocardial infarction (€4916), coronary three-vessel disease (€4659), severely impaired left ventricular function (€6072), or diabetes (€4495). Multivariate analyses identified, even after adjustment for confounding comorbidities, that CKD was a significant and independent predictor of inhospital costs; with each loss of 1 mL/min in the estimated glomerular filtration rate, the expenses for this hospitalization increased by €18 (95% CI: €13–23).[41] Elderly patients with CKD with end-of-life complications are especially costly:[42] during the last 30 days of life, average inpatients costs for elderly CKD patients were approximately US $10,260, with 40.9% receiving surgical interventions, 40.2% experiencing ICU admission, 45.3% undergoing mechanical ventilation, 14.7% receiving resuscitation, and 42.0% receiving dialysis.
In multiple clinical contexts, studies on AKI and associated need for RRT have described the associated costs of treatment. Critically ill patients with AKI requiring dialysis in Finland[43] estimated the cost of AKI per survivor at $80,000 among ICU patients with a 34%–45% mortality.
Post hoc analysis of a prospective, observational study (The Beginning and Ending Supportive Therapy for the Kidney [BEST Kidney] Study) including 53 centers in 23 countries, from September 2000 to December 2000 estimated costs based on staffing, as well as dialysate and replacement fluid, anticoagulation, and extracorporeal circuit.[44] The study found that the median difference in cost between continuous RRT (CRRT) and intermittent RRT was $289.6 (interquartile range 830.8–116.8) per day (greater with CRRT). Costs also varied greatly by region. The authors concluded that cost considerations with RRT are important and vary substantially among centers.
| Conclusions | | |
AKI is a major worldwide problem that is increasingly recognized as a systemic rather than isolated organ pathology. The effects of AKI appear to persist long after the initial insult and represent a large health-care and economic burden.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1], [Table 2], [Table 3]
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