Difference between revisions of "Acute Kidney Injury"

Latest revision as of 20:16, 16 December 2023

General information

The theme of SensUs 2024 is Kidney failure also referred to as acute kidney injury (AKI). Kidney failure is characterized by one or both kidneys losing their renal function, namely, the ability to filter waste matter from the blood. This results in an accumulation of waste in the bloodstream, altering the ionic homeostasis of the blood. There are 5 stages of kidney failure depending on glomerular filtration rate (GFR) which measures the blood filtration rates of the kidneys (in (mL/min)), with the preliminary signs advancing to kidney failure including fatigue, nausea, swelling, etc.^[1] Generally, the clearance of substances that are freely filtered but not secreted or reabsorbed by the kidneys is used to estimate the GFR in clinical settings, with creatinine meeting the criteria.^[2] Creatinine is a product of the metabolism of creatine, which is produced in the liver from three amino acids, methionine, arginine, and glycine, and stored in muscle to be used as a source of energy once phosphorylated. Creatinine is normally excreted through the kidneys. Healthy kidneys are responsible for filtering creatinine out of the bloodstream, as it is a freely filtered metabolite that is not secreted or reabsorbed. Consequently, during kidney failure when the GFR reduces, there is a buildup of high levels of creatinine in the blood. A standard range of serum creatinine levels (SCr) for healthy men is 0.7 - 1.3 mg/dL (61.9 - 114.9 µmol/L), and for healthy women is 0.6 – 1.1 mg/dL (53 – 97.2 µmol/L).^[3] As diet and hydration has a negligible impact on serum creatinine levels, it serves as a reliable indicator of renal function. There is no cure for chronic kidney disease (CKD), although maintaining a proper diet and medications can slow the progression of the disease. A person with kidney failure needs to undergo dialysis treatment or kidney transplantation. These two treatments allow the normal, healthy functioning of the kidneys.^[4]

History of Acute Kidney Injury

Some of the earliest knowledge about kidney and urinary diseases dates all the way back to 9000BC. It comes from the cradle of Western civilization, Mesopotamia, from the cuneiform clay tablets of Acadia, Assyria, and Babylon that contain references to urinary obstruction, stone, cysts, urethritis, stricture, and urethral discharge. In ancient Babylon physicians made diagnoses depending on the appearance of the urine. They treated symptoms with remedies derived from plants or minerals. Drugs were administered by blowing them through a tube into the urethra, most likely also to relieve urinary obstruction, and using alcohol as an anaesthetic. Much of the medical information generated in Mesopotamia was later transported to the Mediterranean, especially to Greece.^{[5] [6]} Except for infections which cause symptoms such as pyuria, pain and fever, at the time (about 450BC), most diseases of the renal parenchyma were unknown in Greek and Roman antiquity. Treatments for uraemia included the use of hot baths, sweating therapies, bloodletting and enemas. First records of urinary diseases are found in the Hippocratic Corpus, a collection of some 60 studies that are believed to represent the work of several medical writers. How much was written by Hippocrates himself remains uncertain. Nevertheless, Hippocrates of Cos (460–377 BCE) is regarded as the father of medicine, and many of the aphorisms attributed to him refer to diseases of the kidney.^{[5] [6] [7] [8] [9] [10]} Even in the Renaissance renal diseases were still not being properly identified and oedema was generally thought to be related to liver disease. In 1827, Richard Bright provided the first, almost complete clinical description of the various forms of acute and chronic glomerulonephritis and showed that they were accompanied by macroscopic changes in the kidneys. Between 1850 and 1885, Frerichs, Klebs and Langhans described the primary glomerular lesions. Scottish chemist Thomas Graham first described dialysis in 1854. He used osmosis to separate dissolved substances and remove water through semi-permeable membranes, although he did not apply the method to medicine.^[10] The first human dialysis machine was constructed in 1943 by Dr Willem Kolff. His work to create an artificial kidney began in the late 1930s when he was working in a small ward at the University of Groningen Hospital in the Netherlands. Kolff’s machine is considered the first modern drum dialyzer. The first patient in the world to be treated by repeated haemodialysis was Clyde Shields in 1960 in Seattle. After the early successes in Seattle, haemodialysis established itself as the treatment of choice worldwide for chronic and acute kidney failure. Membranes, dialyzers and dialysis machines were continuously improved and manufactured industrially in ever-increasing numbers. A major step forward was the development of the first hollow-fibre dialyzer in 1964. This technology replaced the until-then traditional membranous tubes and flat membranes with a number of capillary-sized hollow membranes. This procedure allowed for the production of dialyzers with a surface area large enough to fulfil the demands of efficient dialysis treatment.^{[11] [12]} Over the years that followed, thanks to the development of appropriate industrial manufacturing technologies, it became possible to produce large numbers of disposable dialyzers at a reasonable price. Today, dialyzers are made from entirely synthetic polysulfone, a plastic that exhibits exceptionally good filtering efficiency and tolerability for patients.^[12]

Mechanism of Acute Kidney Injury

Acute kidney injury (AKI), also known as acute renal failure (ARF), is characterized by an abrupt decline in renal function, leading to a reduction in the glomerular filtration rate (GFR) and the subsequent accumulation of nitrogenous waste products in the body.^[13] The clinical signs of acute kidney injury (AKI) are characterized by either an elevation in serum creatinine levels, a decrease in urine output, or both.^[14] The causes of this disorder can then be classified into three categories, namely, pre-renal, intrinsic renal or post renal.^[13]

Pre-renal kidney failure is a term used to describe the condition in which there is a systemic circulation disorder leading to a reduction in renal perfusion and subsequently a reduction in GFR.^[15] Notable causes that can contribute to pre-renal kidney failure include reduced blood volume, peripheral vasodilation, reduced arterial pressure or impaired cardiac function, leading to a reduced cardiac output.^[15] Characterising a condition as pre-renal implies that addressing the root cause of the circulatory disorder, by improving cardiac function or replenishing lost volume, may lead to the restoration of GFR.^[14] However, in most cases, pre-renal failure is often followed by intrinsic renal failure where the GFR of a patient may not be restored, despite addressing pre-renal causes.

Intrinsic renal failure refers to direct damage to the kidney itself and is categorised by the location of the injury, most commonly occuring to the glomerulus or the tubule, and include the interstitial or vascular portions of the kidney.^[16] The typical causes for each include the inflammation and structural damage of the glomerular cells (glomerulonephritis), interstitial cells (acute interstitial nephritis) or the tubular epithelial cells (acute tubular necrosis).^[14] These conditions themselves can be a result of immune complexes from systemic illnesses, ischemic causes such as prolonged periods of severe hypovolemia or hypotension, nephrotoxic causes such as exposure to exogenous or endogenous toxins ^[16], or hypersensitivity reactions to medications such as antibiotics.^[17]

Post-renal failure or obstructive renal failure are caused by disease states downstream of the kidneys resulting in extrarenal obstruction of urinary flow.^[18] These can be related to neurogenic bladder conditions, obstructed urinary catheters, bladder stones, or cancers of the bladder, prostate or ureter.^[18]

The GFR in mL/min can be calculated with the following formula: GFR = ( U_X · V̇ ) / P_X. Here, U_X and P_X are the concentrations of substance X in urine and plasma in mg/mL respectively, with V̇ being the urine flow in mL/min. Ideally X is a substance that is freely filtered but not secreted or reabsorbed by the kidneys, subsequently having the same concentration in the plasma and glomerular filtrate.^[19]These criteria are largely met by creatinine, and the creatinine clearance (C_Cr) obtained from this formula is generally used to measure GFR in clinical practice.^[20] Other diagnostic tools also include serum creatinine levels (SCr) as in the case of renal dysfunction, the creatinine clearance by the kidneys is reduced and therefore the creatinine concentration in the blood rises.^[19]

State of the Art

Matrix

The fluid matrix for biosensor measurements in SensUs 2024 is Interstitial skin fluid (ISF). ISF is the most prevalent fluid in the body, making up 75% of extracellular fluid and 15-25% of body weight.^[21] ISF surrounds cells and tissues, serving as an interface between blood and cells. It may be a source of biomarkers in addition to blood biomarkers, as research shows that 83% of proteins found in blood serum are also present in ISF, but 50% of proteins in ISF are not found in serum.^[22] Due to its accessibility and similarity in composition to serum, ISF is a suitable candidate for continuous monitoring ^[23] and is currently used in clinical settings for continuous glucose monitoring (CGM).

Worldwide research is ongoing on the development of continuous ISF biosensors for analytes such as glucose, urea, and cortisol, with urea being the most relevant to kidney failure.^{[24] [25]}

Continuous glucose monitoring

Glucose sensors are commercially available for continuous monitoring, primarily used in diabetes management.^[26] Most of the CGM biosensors with ISF as a matrix are catalytic biosensors, using glucose oxidase (GOD) as the recognition molecule to bind with glucose.^[26] Microneedle array electrodes have been used for CGM, e.g. by functionalizing them through entrapment of GOD in an electropolymerized film ^[27], or by non-enzymatic amperometric readout.^[28] Other examples of CGM biosensors in ISF include an enzymatic open circuit potential biosensor using GOD ^[29] and an electrochemical glucose sensor composed of electroplated nanoporous platinum.^[30]

Continuous sensing of cortisol

Continuous measurement of cortisol in ISF has been done using the electrochemical impedance (EIS) technique.^[25] This technique involves gold microelectrode arrays functionalized with a self-assembled monolayer (SAM) to fabricate a disposable, electrochemical cortisol immunosensor. ^[25]

Continuous sensing of urea

Urea is an analyte that is relevant for AKI. Gold microneedle arrays have been studied for electrochemical sensing of urea.^[31] Furthermore, wearable potentiometric biosensors have been studied for on-body and on-site monitoring of urea in sweat.^[32]

Creatinine Biosensors

Creatinine is a key indicator of renal function and is measured using various methods. The Jaffe reaction involves creatinine reacting with alkaline picrate to form a measurable orange-red complex, but its drawback lies in low specificity, due to interference from substances like glucose and bilirubin.^[33] Also enzymatic techniques are used for creatinine detection, e.g. creatininase amidohydrolase or creatinine deaminase in conjunction with other enzymes to convert creatinine to creatine and subsequently produce measurable hydrogen peroxide.^[33] While enzymatic sensors are specific and sensitive, they have their drawbacks in terms of lack of stability and sensitivity to changes in pH, temperature and humidity.^[33]

Commercially available analytical systems, such as Abbott's i-STAT system and Nova Biomedical's StatSensor CREAT, leverage enzymes and electrochemistry to provide creatinine measurements, offering a linear correlation between current and creatinine concentration.^[33]

Potentiometric creatinine biosensors have been developed using different immobilization techniques and enzyme combinations. Potentiometric biosensors for creatinine detection rely on creatinine iminohydrolase (CIH) and subsequent ammonia detection. The sensors exhibit a linear range of 0.02 – 20.0 mM and a minimum detection limit of 10 µM, with 30 – 60 s response time.^[34]

Nanomaterials are also being studied for creatinine detection.^[35] Sensors have been demonstrated with sensitivity in the range of 0.2 – 1.4 µM.^[35]

Lastly, a biosensor based on particle motion (BPM) has been studied for continuous creatinine sensing.^[36] The sensor has a competitive format, with anti-creatinine antibodies and creatinine-analogues. The measurement range was 10–1000 μM.^[36]

References