Factors of Acute Kidney Injury

1. Introduction:

Kidneys are the important two paired organs of our body that function normally under the physiological limits. Kidneys may lose its normal functioning under certain circumstances paving way to a disease state of kidney. These kidneys as termed filter units of the body function to excrete waste substances from the body. Similar to the other diseases of the body, kidney diseases result in life threatening dilemma of the society, with inclusive pathological causes and related social norms. In following section various aspects of acute kidney injury (failure) are discussed in detail.

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2. Acute Kidney Injury:

Studies related to ‘’acute kidney failure (ARF)’’ were jeopardized for over past decades due to the conflicting definitions and varied diagnostic criteria of the disease by different investigators, though, all reached to an agreement that a decline in renal function for over the time of hours to days is the distinct characteristic feature of ARF. In the year 2005, an initiative has been taken by Acute Dialysis Quality Initiative and the Acute Kidney Injury Network (AKIN) for replacing the term ‘’Acute Kidney Failure’’ to ’Acute kidney Injury (AKI)’’ (Mehta et al, 2007).However, this definition was further improved in the year 2007, which is mostly accredited to as the RIFLE criteria (Risk-Injury-Failure-Loss of function-End stage renal disease). Moreover, elevated serum creatinine level and deceased urine output are included in the diagnostic criteria. The first three stages of AKI including stage 1 – risk, stage 2 – injury and stage 3 – failure with diagnostic criteria are shown in the Figure 1 (Kellun et al, 2005).

Acute renal failure (ARF) is defined as a rapid and reversible decline in glomerular filtration rate (GFR) ranging from few hours to weeks,that can occur in the setting of previously normal renal function (‘classic’ ARF) or in a patient with pre-existing chronic renal disease (‘acute-on-chronic’ renal failure).

Clinically, ARF is further subcategorized in two distinct types, firstly on the basis of being oliguric (urine output 500 ml/day), and secondly on being dialysis dependence (Schrier et al, 2004). Patients are classified in three categories depending on their risk of renal dysfunction, type of kidney injury, and the degree of kidney failure, which is further associated with two clinical outcomes: Loss and End-stage renal disease (RIFLE). ARF (Loss) is defined as the requirement of renal replacement therapy (RRT) for a period of more than 4 weeks, whereas end-stage renal disease is defined as dependence on dialysis for a period of more than 3 months. Patients with acute renal dysfunction without presenting a baseline measure of renal function are evaluated for the presence of chronic renal disease. The Modification of Diet in Renal Disease formula is used to predict ‘normal’ GFR is there is no evidence of chronic renal disease, which thus is helpful in assessing the severity of the ARF episode (Lameire et al, 2006).

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2.1. Incidence of Acute Kidney Injury:

Evaluation of theaccurateand factual epidemiological characteristics of ARF is hinderedby various reasons such as, lack of a generally accepted definition, gender disparity, issue of lacking consult with a doctor, financial issues in transplantation and treatment and delayed treatment, especially in developing countries, which all together contribute in hampering proper assessment of incidence of acute kidney injury (Cerdá et al, 2008). Furthermore, deviation in catchment populations and methods used for case ascertainment also result in difficulties for ARI evaluation.

The rate of acute kidney injury holds difference in the general population, designated differently as three groups, community-acquired acute kidney injury, the hospitalized patients and critically ill patients of intensive care unit (ICU).

2.1.1. Community Acquired Acute Kidney Injury:

Generally, ARF occurs rarely in community settings. After exclusion of those who suffered chronic renal failure, ARF was found developed in 172 adults per million people (pmp) per year in an unselected population(Singbartl et al., 2000).The incidence ranged between 17 pmp/year and 949 pmp/year for adults (less than 50 years of age) and those aged between 80 years and 89 years, respectively. Acute dialysis was administered to 22 pmp(Liano et al) and it was foundin a research study conducted for over a period of 9 months at 13 tertiary care hospitals in Madrid, Spain that the overall incidence of ARF is about 209 cases pmp. Moreover, it has been reported that community-acquired ARF in the US account for 1% of hospital admissions(Schnermann, 2003). Pre-renal ARF and acute-on-chronic renal failure have been reported to be associated with dehydration particularly in elderly people, use of drugs such as angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers in highrisk patients, and heart failure(Schnermann, 2003). Also, 0.69% of admissions of African Americans were accounted for de novo ARF. The incidence of community acquired ARF in this population was 3.5 times more than that of hospital-acquired ARF; with several patients having underlying medical conditions(Noiri et al., 2001).Disasters in particular earthquakes, many other causes of crush syndromes such as accidents, rhabdomyolysis resulting from infections, coma, and seizures, usage of drugs particularly nonsteroidal anti-inflammatories, and vascular events such as thrombosis of vessels are associated with community-acquired ARF. Furthermore, hemolytic uremic syndrome secondary to infection with Escherichia coli or Shigella is a common cause of ARF, as is poststreptococcal glomerulonephritis in children. Diarrheal diseases, hemolysis, tropical and non-tropical infections, and snake bites are causative factors of ARF in tropical areas such as India and Africa. The overall incidence of obstetric-related ARF has declined for over many years (Melnikov et al., 2001; Wang et al., 2003).

Medicines that are prescribed by traditional healers which mostly comprise mixture of herbs and unidentified chemicals for oral administration or as enemas constitute a distinct class of nephrotoxins in Africa and Asia(Jha V and Chugh2003) 15. Venoms of sea snakes, viper snakes and stinging insects, and raw gallbladder and bile of carp and sheep are present in common animal-derived nephrotoxins. Moreover, common edible plants such as djenkol beans, and mushrooms and medicinal herbs including impila, as well as cat’s clawcomprise botanical nephrotoxins (Melnikov et al., 2001).Nephrotoxicity which is caused by different chemicals can be due to accidental exposure to chemical such as chromic acid in industrial work places or due to use of chemicals such as copper sulphate, ethylene dibromide or ethylene glycol with suicidal or homicidal intent.

2.1.2. Hospital-acquired:

The incidence of hospital acquired ARF surpasses that of community-acquired ARF by 5–10 times, being 0.15–7.20% in hospitalized patients (Nash et al., 2002). Surveysthat are used for hospital-acquired ARF under estimate the true incidence, as cases that include terminal patients are not either referred for treatment for ARF or are not screened for ARF. Out of 311 unselected hospitalized patients with ARF, 22% were referred to a nephrologist in an assessment in unselected patients. Age and comorbidities of patients at presentation influenced the referral(Zuk et al., 2001) and by different referral patterns to the site of care including district general hospital, tertiary referral centre, general ICU, and cardiothoracic ICU. In a prospective hospital-based study of ARF, the estimated incidence with need for RRT was reported to be 203 pmp/year, having patients with acute-on-chronic renal failure inclusive (Metcalfe et al., 2002). A significant elevated level in the incidence of hospital-acquired ARF has been observed over the period of past decades. The US National Center for Health Statistics National Hospital Discharge Survey reported that the number of hospitalizations with a diagnosis of ARF has increased dramatically, from 35,000 in 1979 to more than 650,000 in 2002, depicting an yearly rate of increase of over 13% which may be due tovarious comorbidities of the hospitalized population, increasing age of the population, increased occurrence of risk factors for ARF including chronic kidney disease and diabetes, and furtherprevalent use of intravenous contrast agents for imaging and cardiovascular techniques. Ischemic and/or toxic acute tubular necrosis (ATN) are marked the main causes of hospital-acquired ARF. Most of the time, there involves multi factorial causes including, encompassing postsurgical ATN, chemotherapy-induced ARF, ARF secondary to sepsis, contrast agents or drugs such as antibiotics, allopurinol, nonsteroidal anti-inflammatories and proton-pump inhibitors, and ARF due to a clot or atheroembolism. In spite of the shift in the etiology of hospital-acquired ARF over last few decades, prerenal conditions having manifestationsuch as reduced rates of renal perfusion stays to be leading causative factor of ARF (about 40% of cases). The trend in developed countries towards an elevated incidence of ARF in hospitalized patients due to drugs, different infections and surgeries has been observed in China(Wang et al., 2005)as well as in India (Prakash et al., 2003).

2.1.3. ARF in critically ill patients admitted to the ICU

Patients in ICU, exhibit ARF many times associated with multi-organ dysfunction syndrome (Joannidis&Metnitz, 2005). The findings of a multinational epidemiological study of ARF presented results that showed occurrence of ARF in 1,738 (5.7%) patients during their stay in ICU out of total sample size of 29,269 patients in ICUs of 54 study centers in 23 countries(Uchino et al., 2005), with period prevalence ranging from 1.4% to 25.9% in all study centers. 1,260 (4.2%) of the patients out of overall patients with ARF were treated with RRT. Many ICU patients were considered for ATN in the setting of multi-organ failure (Mehta et al., 2004).

2.2. Pathogenesis:

The pathogenesis of acute kidney injury most importantly comprises two mechanisms that include loss of autoregulation and increased renal vasoconstriction. In experimental animals, acute ischemic injury is found associated with a considerable loss of renal autoregulation (Abuelo, 2007). Also, in case of decrease in renal perfusion pressure, there occurs normal autoregulatory renal vasodilation, evidence has been reported exhibiting renal vasoconstriction in case of ischemic kidney. Moreover, acute ischemic insult has been found associated with rise in the response to renal nerve stimulation (Abuelo, 2007). The increase vasoconstrictor response has been observed to the exogenous norepinephrine and endothelin, in the acute ischemic kidney (Basile, 2007). These vascular anomalies experienced during ischemic kidney are related to the resultant elevation of cytosolic calcium observed in the afferent arterioles of the glomerulus. The pathogenetic role of elevated cytosolic calcium concentration in the afferent arteriole of the ischemic kidney is supported by the observation that intrarenal calcium channel blockers can reverse the loss of autoregulation and the subsequent rise in sensitivity to renal nerve stimulation (Abuelo, 2007). The mitochondrial calcium build-up in the ischemic kidney is found to be reversed by calcium channel blockers administration (Starkov et al., 2004). Moreover, calcium channel blockers have been shown to lessen renal dysfunction and toxicity associated with the immunosuppressive drug cyclosporine following cadaveric renal transplantation, when administrated prior to the ischemic insult (Starkov et al., 2004).

2.2.1. Outer medullary congestion:

The outer medullary congestion of the kidney is yet one of the vascular hallmark of acute renal ischemia. Previous research studies have proposed that the outer medullary congestion of the kidney further worsens the relative hypoxia in the outer medulla and subsequently the hypoxic injury in the S3 segment of the proximal tubule and the thick ascending limb of the Henle loop (Heyman et al., 2010). Up-regulation of adhesion molecules termed related to outer medullary