View source for Acute Kidney Injury

== 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.<ref name="Ref2> End-stage renal disease - Diagnosis and treatment - Mayo Clinic. (2023, October 10). https://www.mayoclinic.org/diseases-conditions/end-stage-renal-disease/diagnosis-treatment/drc-20354538 </ref> 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.<ref name="Ref4"> López-Giacoman, S., & Madero, M. (2015). Biomarkers in chronic kidney disease, from kidney function to kidney damage. World Journal of Nephrology, 4(1), 57. https://doi.org/10.5527/wjn.v4.i1.57 </ref>
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).<ref name="Ref5"> Creatinine blood test. (n.d.-b). Mount Sinai Health System. https://www.mountsinai.org/health-library/tests/creatinine-blood-test#:~:text=Normal%20Results,less%20muscle%20mass%20than%20men </ref> 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.<ref name="Ref6">World Kidney Day. (2019, June 7). Chronic Kidney Disease - World Kidney Day. World Kidney Day -. https://www.worldkidneyday.org/facts/chronic-kidney-disease/ </ref>

== 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.<ref name = "Ref7"> Geller, M. J., and Cohen, S. L. Kidney and urinary tract disease in ancient Babylonia, with translations of the cuneiform sources. Kidney International 1995; 47: 1811–1815.</ref> <ref name = "Ref8"> Mujais, S. The future of the realm: medicine and divination in ancient Syro-Mesopotamia. Am J Nephrol 1999; 19: 133–139.</ref>
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.<ref name = "Ref7"/> <ref name = "Ref8"/> <ref name = "Ref9">Diamandopoulos, A. A. Twelve centuries of nephrological writings in the Graeco-Roman world of the Eastern Mediterranean (from Hippocrates to Aetius Amidanus). Nephrol Dial Transplant 1999; 14[Suppl 2]: 2–9.
</ref> <ref name = "Ref10">Marandola, P., Musitelli, S., Jallous, H., Speroni, A., de Bastiani, T. The Aristotelian kidney. Am J Nephrol 1994; 14: 302–306.
</ref> <ref name = "Ref11">Marketos, S. G., Eftychiadis, A. G., Diamandopoulos, A. Acute renal failure according to ancient Greek and Byzantine medical writers. J R Soc Med 1993; 86: 290–293.</ref> <ref name = "Ref12">F Reubi, [On the history of kidney disease], Schweiz Med Wochenschr 1987; 7;117(10): 369-76
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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.<ref name = "Ref12"/> 
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.<ref name = "Ref13">History of the kidney disease treatment, https://www.sgkpa.org.uk/main/history-of-the-kidney-disease-treatment
</ref> <ref name = "Ref14">The History of Dialysis, https://www.fresenius.com/history-of-dialysis
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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.<ref name = "Ref14"/>

== 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.<ref name = "Ref15"> Lote, C.J., Harper, L. and Savage, C.O. (1996) ‘Mechanisms of acute renal failure’, British Journal of Anaesthesia, 77(1), pp. 82–89. doi:10.1093/bja/77.1.82.</ref> 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.<ref name = "Ref16">Ronco, C., Bellomo, R. and Kellum, J.A. (2019) ‘Acute kidney injury’, The Lancet, 394(10212), pp. 1949–1964. doi:10.1016/s0140-6736(19)32563-2
</ref> The causes of this disorder can then be classified into three categories, namely, pre-renal, intrinsic renal or post renal.<ref name = "Ref15"/> 

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.<ref name = "Ref17"> Kellum, J.A. and Lameire, N. (2013) ‘Diagnosis, evaluation, and management of Acute Kidney Injury: A KDIGO summary (part 1)’, Critical Care, 17(1), p. 204. doi:10.1186/cc11454. </ref>  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.<ref name = "Ref17"/> 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.<ref name = "Ref16"/> 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.<ref name = "Ref18"> Sharfuddin, A.A. et al. (2012) ‘Acute kidney injury’, Brenner and Rector’s The Kidney, pp. 1044–1099. doi:10.1016/b978-1-4160-6193-9.10030-2. 
</ref> 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).<ref name = "Ref16"/> 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 <ref name = "Ref18"/>, or hypersensitivity reactions to medications such as antibiotics.<ref name = "Ref19">Praga, M. and González, E. (2010) ‘Acute interstitial nephritis’, Kidney International, 77(11), pp. 956–961. doi:10.1038/ki.2010.89. </ref>

Post-renal failure or obstructive renal failure are caused by disease states downstream of the kidneys resulting in extrarenal obstruction of urinary flow.<ref name = "Ref20">Raup, V.T., Chang, S.L. and Eswara, J.R. (2018) ‘Post-renal acute kidney injury: Epidemiology, presentation, pathophysiology, diagnosis, and management’, Core Concepts in Acute Kidney Injury, pp. 247–256. doi:10.1007/978-1-4939-8628-6_16. 
</ref> These can be related to neurogenic bladder conditions, obstructed urinary catheters, bladder stones, or cancers of the bladder, prostate or ureter.<ref name = "Ref20"/>

The GFR in mL/min can be calculated with the following formula: '''GFR''' = ( U<sub>X</sub> · V̇ ) / P<sub>X</sub>. Here, U<sub>X</sub> and P<sub>X</sub> 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.<ref name = "Ref21">Pocock, G., Richards, C.D. and Richards, D.A. (2013) Human physiology. Oxford: Oxford University Press.</ref>These criteria are largely met by creatinine, and the creatinine clearance (C<sub>Cr</sub>) obtained from this formula is generally used to measure GFR in clinical practice.<ref name = "Ref22">Delgado, C. et al. (2022) ‘A unifying approach for GFR estimation: Recommendations of the NKF-ASN task force on reassessing the inclusion of race in diagnosing kidney disease’, American Journal of Kidney Diseases, 79(2). doi:10.1053/j.ajkd.2021.08.003.</ref> 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.<ref name = "Ref21"/>

== 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.<ref name = "Ref24">Samant, P. P., Niedzwiecki, M. M., Raviele, N., Tran, V., Mena-Lapaix, J., Walker, D. I., Felner, E. I., Jones, D. P., Miller, G. W., & Prausnitz, M. R. (2020). Sampling interstitial fluid from human skin using a microneedle patch. Science Translational Medicine, 12(571). https://doi.org/10.1126/scitranslmed.aaw0285
</ref> 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.<ref name = "Ref25">Samant, Pradnya P, and Mark R Prausnitz. “Mechanisms of Sampling Interstitial Fluid from Skin Using a Microneedle Patch.” Proceedings of the National Academy of Sciences of the United States of America, 2018, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939066/ 
</ref> Due to its accessibility and similarity in composition to serum, ISF is a suitable candidate for continuous monitoring <ref name = "Ref23">Friedel, M., Thompson, I. a. P., Kasting, G. B., Polsky, R., Cunningham, D., Soh, H. T., & Heikenfeld, J. (2023b). Opportunities and challenges in the diagnostic utility of dermal interstitial fluid. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-022-00998-9</ref> 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.<ref name = "Ref26">Chen, Q., Zhao, Y., & Liu, Y. (2021b). Current development in wearable glucose meters. Chinese Chemical Letters, 32(12), 3705–3717. https://doi.org/10.1016/j.cclet.2021.05.043</ref> <ref name = "Ref27">Venugopal, M., Arya, S. K., Chornokur, G., & Bhansali, S. (2011b). A realtime and continuous assessment of cortisol in ISF using electrochemical impedance spectroscopy. Sensors and Actuators A: Physical, 172(1), 154–160. https://doi.org/10.1016/j.sna.2011.04.028
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=== Continuous glucose monitoring ===
Glucose sensors are commercially available for continuous monitoring, primarily used in diabetes management.<ref name = "Ref28">Johnston, L. et al. (2021) ‘Advances in biosensors for continuous glucose monitoring towards wearables’, Frontiers in Bioengineering and Biotechnology, 9. doi:10.3389/fbioe.2021.733810. 
</ref> 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.<ref name = "Ref28"/> Microneedle array electrodes have been used for CGM, e.g. by functionalizing them through entrapment of GOD in an electropolymerized film <ref name = "Ref30">Sharma, S. et al. (2016) ‘Evaluation of a minimally invasive glucose biosensor for continuous tissue monitoring’, Analytical and Bioanalytical Chemistry, 408(29), pp. 8427–8435. doi:10.1007/s00216-016-9961-6. 
</ref>, or by non-enzymatic amperometric readout.<ref name = "Ref31">Lee, S.J. et al. (2016) ‘A patch type non-enzymatic biosensor based on 3D sus micro-needle electrode array for minimally invasive continuous glucose monitoring’, Sensors and Actuators B: Chemical, 222, pp. 1144–1151. doi:10.1016/j.snb.2015.08.013. 
</ref> Other examples of CGM biosensors in ISF include an enzymatic open circuit potential biosensor using GOD <ref name = "Ref32">Song, Y. et al. (2016) ‘Design and preparation of open circuit potential biosensor for in vitro and in vivo glucose monitoring’, Analytical and Bioanalytical Chemistry, 409(1), pp. 161–168. doi:10.1007/s00216-016-9982-1. 
</ref> and an electrochemical glucose sensor composed of electroplated nanoporous platinum.<ref name = "Ref33">Yoon, H. et al. (2018) ‘Wearable, robust, non-enzymatic continuous glucose monitoring system and its in vivo investigation’, Biosensors and Bioelectronics, 117, pp. 267–275. doi:10.1016/j.bios.2018.06.008.
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=== Continuous sensing of cortisol ===
Continuous measurement of cortisol in ISF has been done using the electrochemical impedance (EIS) technique.<ref name = "Ref27"/> This technique involves gold microelectrode arrays functionalized with a self-assembled monolayer (SAM) to fabricate a disposable, electrochemical cortisol immunosensor. <ref name = "Ref27"/>

=== Continuous sensing of urea ===
Urea is an analyte that is relevant for AKI. Gold microneedle arrays have been studied for electrochemical sensing of  urea.<ref name = "Ref35">Şenel, M., Dervisevic, M., & Voelcker, N. H. (2019). Gold microneedles fabricated by casting of gold ink used for urea sensing. Materials Letters, 243, 50–53. https://doi.org/10.1016/j.matlet.2019.02.014
</ref> Furthermore, wearable potentiometric biosensors have been studied for on-body and on-site monitoring of urea in sweat.<ref name = "Ref36">Ibáñez-Redín, G., Cagnani, G. R., Gomes, N. O., Raymundo‐Pereira, P. A., Machado, S. a. S., Gutierrez, M. A., Krieger, J. E., & Oliveira, O. N. (2023). Wearable potentiometric biosensor for analysis of urea in sweat. Biosensors and Bioelectronics, 223, 114994. https://doi.org/10.1016/j.bios.2022.114994
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== 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.<ref name = "Ref38">Creatinine - SensUS Wiki. (n.d.). https://wiki.sensus.org/index.php?title=Creatinine
</ref> 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.<ref name = "Ref38"/> 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.<ref name = "Ref38"/>

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.<ref name = "Ref38"/> 

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.<ref name = "Ref37">Pundir, C., Kumar, P., & Jaiwal, R. (2019b). Biosensing methods for determination of creatinine: A review. Biosensors and Bioelectronics, 126, 707–724. https://doi.org/10.1016/j.bios.2018.11.031
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Nanomaterials are also being studied for creatinine detection.<ref name = "Ref40">Narimani, R., Esmaeili, M., Rasta, S. H., Khosroshahi, H. T., & Mobed, A. (2020). Trend in creatinine determining methods: Conventional methods to molecular‐based methods. Analytical Science Advances, 2(5–6), 308–325. https://doi.org/10.1002/ansa.202000074
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Sensors have been demonstrated with sensitivity in the range of 0.2 – 1.4 µM.<ref name = "Ref40"/>

Lastly, a biosensor based on particle motion (BPM) has been studied for continuous creatinine sensing.<ref name = "Ref42">Yan, J. et al. (2020) ‘Continuous small-molecule monitoring with a digital single-particle switch’, ACS Sensors, 5(4), pp. 1168–1176. doi:10.1021/acssensors.0c00220.
</ref> The sensor has a competitive format, with anti-creatinine antibodies and creatinine-analogues. The measurement range was 10–1000 μM.<ref name = "Ref42"/>

== References ==