Chronic kidney disease and acute kidney injury

1. End stage renal disease (ESRD) - CKD and associated vascular calcification (CVD): CKD is a condition that involves pathological anomalies in the structure or the functioning of the kidney when present for longer than three months and attribute noticeable health implications [2]. There can be several instances of abnormality in the structure and function of the kidney but without any health implications [2]. Therefore, CKD is a diagnosis that involves implications on health [2]. In most CKDs, there is a decline in the metabolic functions and even in endocrine or excretory systems [3]. There can be incidences of acute kidney injury in most types of CKD [3]. With the onset of AKI in CKD patients, the process of kidney failure is accelerated [3]. With most types of CKD, there is an associated risk of cardiovascular disease incidence [3]. Irrespective of race, gender, or etiology of patients, there are three main types of associated diseases with CKD [3]. The first is an incidence of drug toxicity [3]. The risk of interactions of drug is commonplace in CKD and the pharmokinetic data of drug excreted in the kidney require adjustment of dosages for patients with drug intolerance and drug toxicity [3]. The second is the incidence of endocrine and metabolic disorders and abnormalities [3]. With the decline in the level of GFR, there is development of several conditions such as anemia, bone and mineral disorders, acidosis etc which are all induced by complications in the endocrine system [3]. The third is the most common which is the risk of cardiovascular disease in CKD [3]. The reduction in the GFR is found to be an important precursor for the development of CVD and mortality associated with it [3]. Kidney failure and acute kidney injury are also resultants of the incidence of reduction in GFR [2, 3]. Although research has not established definitively that the CKD is a marker or a causative factor of CVD, the incidence of CVD morbidity and mortality has a clear association with CKD [4].

The most common CKD is the end stage renal disease (ESRD) and it is associated with CVD and coronary artery calcification [4].The incidence of CVD involves the Framingham risk factors that are listed as its causative factors [4]. Of these, the first and the most prevalent causative factor is diabetes, which is a co-morbid condition of ESRD [4]. The second factor is hypertension and it is a frequently co-morbid incidence in ESRD [4]. The common reasons in the pathophysiology of CKD with CVD include arterial calcification and extensive medial calcification [4]. These are additionally responsible for cardiovascular mortality in CKD [4].

Etiology: Framingham risk factors are commonly attributed with the incidence of CKD and cardiovascular mortality [4]. However, scientists have found that the Framingham risk factors do not suffice for the complete understanding of CVD and co-morbidity with CKD [4]. In patients with ESRD, irrespective of their age, calcification in the coronary artery is much common [4]. The incidence of coronary artery calcification has rapid progression in almost all cases [4]. With the presence of ESRD, the calcification is higher [4]. Medial thickness of calcification is much greater in ESRD patients as compared to non-ESRD patients [4]. Research has demonstrated that one of the probable reasons for increase in cardiovascular mortality in ESRD patients is the incidence of large vessel disease [4]. Additionally, scientists have found that there is an elevation in the levels of myocardial oxygen demand, afterload in the vascular system, subendocardial ischemia, pulse pressure, pulse wave velocity etc [4]. The increase in these factors is included in the elastic arteries of the carotid and aorta along with the femoral arteries [4]. Studies have illustrated that there is an increase in excessive atherosclerosis in patients with ESRD [4]. In patients with ESRD, the likelihood of atherosclerotic lesions being more heavily calcified is higher [4]. Calciphylaxis is a common occurrence exclusively in patients with ESRD [4]. Calcific uremic arteriolopathy is a disorder in which there are medial calcification sites leading to skin necrosis ultimately [4].

Pathogenesis: Scientists have not completely understood the pathogenesis of vascular calcification in CKD [4]. The occurrence of this disease is almost similar to the general population in patients with CKD as well [4]. It has several causative factors to which the generation of vascular calcification may be attributed [4]. Studies have found that there are both traditional and uremic-specific risk factors for vascular calcification in patients with CKD [4]. The role of these causative risk factors is yet to be determined in research [4]. Primarily, the non-traditional factors include hyperphosphatemia, hypercalcimia, elevated homocysteine levels, oxidized LDLs, elevated C-reactive proteins etc [4]. The duration for which dialysis is carried out along with the data of disorders of mineral metabolism provide enough insight on the occurrence of vascular calcification of CKD [4]. In most patients with CKD, there is a direct correlation between disorders of the mineral metabolism and vascular calcification [4]. The disorders of mineral metabolism would include abnormal levels of calcium and phosphorous in serum [4]. It most cases of CKD, patients with a progression in the disease tend to develop pathological elevation in parathyroid hormone (PTH) [4]. At the initial stages of disease onset, the patients typically have hypocalcemia [4]. However, these patients will develop hypercalcimia when administered with vitamin D or calcium [4]. Studies have demonstrated that in rats, when CKD is induced in vitro or naturally occurring in vivo, they tend to develop medial calcification [4]. However, they do not develop atherogenic or intimal calcification [4]. The management for such calcification generally includes the administration of phosphate binders [4]. However, studies have found that in rat models, there is a reduction in the calcification of the aortic vasculature when administered with non-calcium containing phosphate binders [4]. In the rat models that were administered with calcium containing phosphate binders there was the occurrence of hypercalcimia [4]. Research has found that in these models, there is an occurrence of altered mineral homeostasis or hyperparathyroid bine disease of the secondary type [4]. These findings in literature indicate that there is an important role for the excess intake of calcium in the pathogenesis of vascular calcification in patients with CKD [4]. Altered mineral metabolism also results from the intake of calcium when the rats are treated with less-calcimic drugs [4]. In the pathology of medial vascular calcification, these factors play a vital role as demonstrated in research [4]. Thus, research supports a positive correlation between disorders of mineral metabolism and vascular calcification occurring in CKD patients [4]. At the cellular level, there are several genetic mutations and deletions that can lead to the development of calcification in CKD [4]. This finding is supported by the fact that several studies have demonstrated the presence of proteins of the bone in specific areas from which the specimens of calcification were taken [4]. This was true of both coronary and peripheral arteries [4]. The cells of the smooth muscles also have the ability to be mineralized in vitro similar to the synthesis of osteoblasts [4].Thus, the study of cellular pathogenesis indicates that the intimal and medial calcification processes are similar to osteogenesis [4]. Most non-traditional risk factors of cardiovascular disease and vascular calcification in CKD that are also indicative of mineralization that include elevation of phosphorous, parathyroid hormone-related peptide, parathyroid hormone, calcitrol, lipoproteins etc [4].

Acute kidney Injury

Acute kidney injury (AKI) is the novel terminology in consensus for acute renal failure [5]. This is a disorder that is typically characterized by rapid decrease in the excretory function of the renal system [5]. There is an accumulation of products of metabolism of nitrogen such as creatinine and urea [5]. There is an additional accumulation of unmeasured wastes of a similar nature [5]. The clinical presentations of AKI include a decrease in the output of urine which may or may not manifest in the clinical setting as a symptom, metabolic acids accumulation, and a noticeable elevation in the serum phosphate and potassium concentrations [5]. In recent times, the term acute renal failure has been replaced with AKI in order to lay emphasis on the fact that there exists a continuum in injuries to the kidney prior to the manifestation of the clinical symptoms [5]. The common clinical presentations of suuficient loss of excretory function of the kidney thus occur much later in stage and can be measured by lab procedures [5].

Etiology and Epidemiology: ‘The Acute Dialysis Quality Initiative’ has reached a consensus for the terminology and definition of AKI post the findings mentioned above [5]. They have developed criteria that are somewhat definitive for the diagnosis of AKI [5]. This criterion is popularly known as the RIFLE (risk, injury, failure, loss, end stage) criterion [5]. In general, the condition of AKI is a common challenge in terms of diagnosis and therapy for most physicians [5]. Thus, the diagnosis and therapeutic methods adopted bear a significant impact on the prognosis as well [5]. It has been found that the incidence of AKI has a regular implication from geographic settings as well [5]. The causative factors of AKI are included in the area of occurrence of the disease [5]. In particular developing countries, for example, hypovolemia which occurs as a secondary symptom to diarrhea is a common occurrence [5]. Certain conditions occur more in hospitals as compared to other situations [5]. Therefore, before arriving at a specific diagnostic method, it is important to consider the local epidemiology or geographical context as some of the diagnostic methods may trigger acute kidney injury [5]. Commonly, most physicians are familiar with two ideas that are vital to AKI namely acute tubular necrosis and prerenal azotaemia [5]. Acute tubular necrosis is essentially illustrated by a condition of intrinsic kidney injury that is resulted from persistent and/or severe form of hyperperfusion of the kidneys [5]. However, scientists have suggested that this approach may be flawed due to the basic idea that the term acute tubular necrosis largely is a combination of a diagnosis made on histological basis and sometimes (rarely) confirmed by a biopsy [5]. This makes it impossible to verify scientifically and may not contain clinical syndrome of complex mechanisms [5]. It is primarily flawed as it fails to represent the continuum of the condition of acute kidney injury [5].

Pathophysiology: The inflammatory diseases of the kidney parenchyma have a complex pathogenesis mechanism [5]. This complex mechanism has implications on almost all aspects of the inflammatory system that are innate and mediated by the antibody [5]. They are additionally mediated in the immune system cells and lymphatic cell system [5]. Studies focusing on animal models to decipher the pathways and mechanisms of development of the AKI and acute occlusion of the renal artery have led to revelations of the common pathways of disease development even in associated ischemic conditions [5]. The coagulation system appears to be activated locally and the infiltration of leukocytes into the kidney is also a common occurrence [5]. There is the presence of injury to the endothelium and expression of adhesion molecules is a constant occurrence as well [5]. This is often accompanied by the release of cytokines, induction of toll-like receptors, and activation of pathways of intrarenal vasoconstrictor along with the induction of apoptosis [5]. There may be an associated occurrence of modifications such as loss of polarity inversion in the tubular cells or adhesion loss to the basement membrane [5]. The injury to the kidney or renal injury has an apparent ability of triggering an injury to an organ elsewhere [5]. The pathways to these are, however, unclear and emphasize the complexity of the biological response to acute kidney injury [5]. However, although sepsis is a common cause of AKI, this model of ischemia has very little relevance to these illnesses including sepsis [5]. Sepsis is one of the most common causes of acute kidney injury and acute renal injury, especially in inpatients of the hospital and those in intensive care [5]. This model also does not have much relevance to the occurrence of renal perfusion which is a common occurrence in AKI [4, 5]. In most patients of AKI in modern hospital settings, sepsis and major surgery are common causes for the occurrence of AKI [4, 5]. However, the ischemic model used for the diagnosis by most clinicians is flawed and irrelevant [5]. Renal perfusion which is a common occurrence in AKI caused by major surgeries is not of relevance to this model [5]. AKI is additionally triggered by acute decompensated heart failure, open heart surgeries etc [5]. In any of these situations, however, there is an absence of occlusion of the artery [5].

Neurohormonal pathogenesis: The activation of the systemic nervous system and procurement of neurohormonal responses which are unique to the location of kidney and present in AKI are activated [5]. The rennin-angiotensin-aldosterone system, feedback of the glomerulus, and the renal sympathetic system are also activated [5]. The framework of diagnosis and pathophysiology generated from this knowledge has led to the idea that in situations of sepsis, the infection results in the induction of nitric oxide synthase [5]. Water retention also occurs due to the activation of vasopressin and arginine [5]. The most popularly studied form of AKI includes the hepatorenal syndrome [5]. The changes are mostly histopahtological and of renal origin and is essential in natural circumstances [5]. Decrease in systemic blood pressure and vasodilation are key events in the prognosis [5].

Diagnosis: The concentrations of creatinine and urea are primary diagnostic parameters [5]. Acute kidney injury is mostly asymptomatic in nature [5]. It does not contain any characteristic clinical findings and the diagnosis is typically carried out in the presence of other illnesses of acute nature [5]. Abnormal serum creatinine and urea levels are the primary diagnostic analytes apart from clinical presentations [5].

Triggers of AKI (Sepsis-induced AKI): Severe sepsis is typically the most important factor for the development of acute renal injury [6]. Sepsis induced AKI is associated with high rates of mortality in those patients who are critically ill [6]. The most important characteristic of septic AKI is the rapid and noticeable decrease in the capacity of the kidney of filtration of blood or even in the elimination of nitrogenous wastes [6]. The evolution of this occurs for days after the onset of sepsis [5, 6]. There are severe limitations in the understanding of mechanisms of pathophysiology which has led to the preclusion in the development of effective therapeutic mechanisms for AKI [5, 6].

Early diagnosis and management of sepsis-induced AKI: Control of early infectious triggers is an effective treatment method for severe septic AKI [6]. Supportive care, vasopressors, fluids of intravenous nature, and renal replacement therapy (RRT) are all effective methods of therapy [6]. The kidney responds to sepsis by cellular adaption [6]. At the cellular level, the innte immune system responds to the infectious pathogens that trigger an immunological response [6]. Lipopolysaccharides and other similar pathogenic proteins are released into the cell at the site of infection [6]. The tubular, vascular, and glomerular functions of the kidney are affected by the pathogen associated molecular patterns into the bloodstream [5, 6]. The primary methods of management of the disease in the patients with septic kidney injury are:

1.Systemic blood pressure: Arterial blood pressure increases complications in severe cases of infection [6]. This has the likelihood of contributing to the development and progression of AKI [6]. Thus, the first step of management is to measure the optimal blood pressure target that we require to prevent damage to the kidney [6].

2.Fluid management and central venous pressure: The therapeutic mainstay for AKI is the administration of intravenous fluids [6]. These include the administration of vasopressors and inotropes [6]. These are often guided by physiological endpoints [6].

3.Vasopressor therapy: Vasopressors can restore blood pressure in septic patients to a reliable extent [6].

4.Renal replacement therapy: continuous RRT is more efficient than intermittent RRT [6].

5.Red blood cell infusion: The administration of RBCs is a common therapeutic method for the treatment of AKI [6].

References:

• Sara N Davidson, edited by Judith A, “Chronic kidney disease: physiological impact of chronic pain,” Geriatrics, 2007, 62(2): 17-23
• Astor BC, Matsushita K, Gansevoort RT, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts, Kidney Int. 2011, 79:1331–1340
• Matsushita K, van der Velde M, Astor BC, et al., “Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis,” Lancet, 2010, 375:2073–2081
• Sharan M. Moe, Neal X. Chen, “Pathophysiology of vascular calcification in chronic kidney disease,” Circ Res., 2004, 95: 560-567

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