International Society of Nephrology’s 0by25 initiative (zero preventable deaths from acute kidney injury by 2025): focus on diagnosis of acute kidney injury in low-income countries

International Society of Nephrology’s 0by25 initiative (zero preventable deaths from acute... In developing countries with limited medical infrastructure, preservation and recovery of renal function following acute kidney injury (AKI) is difficult. In conjunction with clinical presentation, rapid measurement of renal function is essential for early diagnosis and management. Especially in low- and middle-income countries, simple interventions such as hydra- tion and avoidance of toxins have the highest probability of recovery. In such contexts, measurement of urine volume and osmolality and serum creatinine with point-of-care devices and saliva urea nitrogen dipsticks can be valuable. This review aims to identify currently available methodologies to assist in reaching the ambitious goal of the 0by25 initiative to elimin- ate all preventable deaths from AKI by 2025. Key words: AKI, biomarkers, blood and saliva urea nitrogen, creatinine, guidelines, intensive care, systematic review Introduction [1, 5], with dehydration and hypotension being the most com- mon cause in recently published data [3]. Acute kidney injury (AKI) is increasingly recognized as a major In LMIC, a large fraction of newly occurring community- public health challenge, particularly in less privileged areas of acquired AKI is due to causes, which have a substantial poten- the world. Despite technological progress and substantial pre- tial of reversibility with simple interventions [2, 5]. Infectious ventive efforts, the incidence of AKI in these countries remains diseases (mainly gastroenteritis associated with diarrhea, mal- high with an estimated 13.3 million cases per year (85% of aria and leptospirosis) and obstetric complications are the lead- which in developing countries), and it was further estimated that around 1.7 million deaths can be attributed to AKI [1–4]. ing causes of AKI, followed by animal venoms and natural herbal medicines [2]. Although treating the underlying cause is Although AKI in developed countries with sophisticated med- of prime importance, death as a consequence of AKI may often ical infrastructure is predominantly a disease found in hospital- ized, elderly and very sick patients, in low- and middle-income be prevented by simple interventions such as oral rehydration countries (LMIC) it is largely a community-acquired condition or immediate temporary dialysis. Given the potential Received: August 17, 2016. Accepted: November 9, 2016 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Diagnosis of AKI in low-income countries | 13 reversibility of AKI with early intervention, early diagnosis is of of devices with a substantially smaller footprint has become particular importance. However, given the possibility of causing possible in remote environments. Some of these POCT devices an even greater risk of adverse outcomes by fluid overloading can be utilized in conjunction with smart phones, which auto- patients where rehydration is not indicated [6], accurate diag- matically digitize results and communicate via text message or nostic tools are central to safely intervene at an early stage. the world-wide-web. These devices are available to measure Provision and utilization of early diagnostic tools in remote biomarkers of a broad range of diseases and can be used in areas without an adequately trained medical and nursing infra- blood, plasma, sweat, urine and saliva specimens. In combin- structure and often lacking power sources is a major deterrent ation with medical history and examination, and routine diag- to change [7, 8]. Even when diagnostic tools and therapeutic de- nostic instruments, point-of-care techniques reveal a wide vices are available, specific training of primary healthcare pro- range of applications and enable care to be delivered to a large viders can be difficult. A detailed review on risk factors, number of patients in LMIC. As current diagnostic measures are management and all associated challenges has recently been based, in part, on the use of serum creatinine (RIFLE [11], AKIN published [9]. [12] and KDIGO Guidelines [13]), measurement of this parameter The International Society of Nephrology’s AKI initiative aims is crucial. to prevent all avoidable death from AKI by 2025 (0by25) [2]. A re- Point-of-care devices have already found use in the monitor- cently conducted and published Global Snapshot study as- ing of the administration of nephrotoxic agents in radiologic sessed during a 10-week period the whole range of AKI as facilities [14], during surgery, to monitor the effects of exposure reported by 322 caregivers from all over the world on 4018 diag- to nephrotoxic drugs in oncology or to dose antibiotics [14, 15]. nosed patients [3]. Currently, pilot projects are being designed Experience with these devices in remote areas without tech- and launched that aim to assess the management of AKI in a nical and medical infrastructure corroborates their usefulness real-life setting in low-income countries and to identify areas of [16]. However, it is imperative that the use of POCT devices in improvement. developing countries needs to be consistent with practices in In the context of the International Society of Nephrology’s the developed world ([17]; Table 1). Furthermore, it is important 0by25 initiative, this report aims to evaluate currently available that POCT devices need to be able to connect to commonly used methods for early diagnosis of AKI in remote areas with inad- data processing devices (i.e. smartphones, tabloids, computers) equate medical infrastructure. in order to transmit or store data for future use, such as clinical observation and monitoring, and/or clinical research. Point-of-care testing Diagnosis of AKI This manuscript will focus on point-of-care testing (POCT) only. Thus, we will not discuss other potential methods of measuring AKI diagnosis is mainly based on changes in urine volume, renal function that are expensive and are not used on a routine plasma creatinine and blood urea nitrogen (BUN). Assessments basis for clinical care, including low molecular weight proteins of urine osmolality (or specific gravity), urinary sodium concen- such as cystatin C, up-regulated proteins such as NGAL, KIM-1, tration and fractional excretion of sodium and urea possibly LFABP and IL-18, and tubular enzymes that are excreted in the have value to diagnose conditions such as dehydration and urine as a results of tubular acute injury. Additionally, a new hypotension (particularly important for developing countries generation of biomarkers useful in the diagnosis of AKI, the cell where these conditions are the most common cause of AKI). cycle arrest biomarkers, require mentioning and are currently Current KDIGO recommendations (Table 2) have found broad under intensive research will not be discussed in this manu- acceptance [13]. However, the need for blood draws and urine script [10]. collection is generally difficult in remote villages. The development of new generation diagnostic devices and Herein, we briefly discuss clinical presentation, and urine-, biomarkers has widened the available methodologies needed to blood- and saliva-based biomarkers of interest for the diagnosis make early diagnosis outside of hospitals. However, their use and assessment of severity of AKI. demands the development of a new infrastructure to operate the devices and communicate results. Some diagnostic elem- Clinical presentation and medical history ents, such as urine dipsticks, remain available and are invalu- able for screening purposes or in the detection of suspected The clinical history is essential in the diagnosis of AKI, usually disease. Finally, with the advancement of technology and preceded by infection-related vomiting and diarrhea leading to strong consumer support of the ‘smaller is better’ concept, use dehydration and hypovolemia, or ingestion of drugs (including Table 1. Practice recommendations of the American Association for Clinical Chemistry and the National Academy for Clinical Biochemistry on the use of point-of-care technology devices Development and maintenance of a comprehensive quality assurance program, including operator training and competency assessment, quality control, equipment maintenance, reagent storage, periodic correlation of results with a central laboratory and troubleshooting of sig- nificant discrepancies or errors. An interdisciplinary work group including physicians and laboratory professionals. Close collaboration between the laboratory director and POCT users to monitor testing and to investigate deviations, complaints or incidents is essential. Training programs and continuing education of those involved on dissemination of knowledge of recent innovations and limitations in POCT devices and testing. Data management as a mechanism to improve the quality of POCT. Concurrent central laboratory creatinine testing of the same samples is recommended for the early stages of program development and conduct of regular quality assurance studies. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 14 | J.G. Raimann et al. Table 2. KDIGO: definition and classification of AKI Table 3. Pathophysiological correlates of urine discoloration (based on [20]) AKI Serum creatinine Urine output stage Pink Hematuria, hemoglobinuria and myoglobinuria; massive uric acid crystalluria 1 1.5–1.9 times baseline <0.5 mL/kg/h for Red Hematuria, hemoglobinuria and myoglobinuria; OR 6–12 h porphyrinuria and alkaptonuria (turns black on 0.3 mg/dL (26.5 mmol/L) increase standing) 2 2.0–2.9 times baseline <0.5 mL/kg/h for Brown Hematuria, hemoglobinuria and myoglobinuria; 12 h jaundice 3 3.0 times baseline <0.3 mL/kg/h for Black Hematuria, hemoglobinuria and myoglobinuria OR 24 h White (milky) Chyluria Increase in serum creatinine to OR Velvet Urinary infection (certain strains of Escherichia coli) 4.0 mg/dL (353.6 mmol/L) Anuria for 12 h OR Initiation of renal replacement therapy does render these diagnostic methods less practical in remote OR settings. It may, however, be envisioned that future techno- In patients <18 years, decrease in logical innovations such as one allowing the imaging of hel- eGFR to<35 mL/min/1.73 m minth eggs using mini-microscopes constructed from webcams Known or presumed to have occurred during the prior 7 days. and mobile phone cameras [24] will one day allow for affordable Within the preceding 48 h. urinary microscopy in remote settings in developing countries. eGFR, estimated glomerular filtration rate. It may further be envisioned that more sophisticated approaches, possibly with electronic transfer of images or auto- mated methods of diagnosis, could at one point enable the rou- tine use of urinary microscopy in medically isolated settings. herbal medicines), snake bites, parasitic diseases such as mal- aria, obstetric complications and other etiologies. Often, the clinical presentation is dominated by the underlying disease Urine osmolality/specific gravity and the AKI-specific symptoms are lost within a myriad of Reports of changes in frequency of urination and urinary vol- disease-specific symptoms [4, 18]. ume and color provide valuable information (see Table 3;[25]) Oliguria is not always present in AKI, but when present pro- and it is well established that dehydration causes increases in vides valuable information. KDIGO guidelines define a reduction serum and urine osmolality. Work using the diagnostic value of of urine volume as an independent criterion for AKI diagnosis color scales to diagnose urinary osmolality and possible dehy- (Table 2). It has been reported that mortality is highest when dration deserves mentioning in this context [26]. Measurement both creatinine elevation and oliguria are present [19]. A recent of urinary osmolality requires an osmometer or a refractometer. publication in critically ill patients showed that an assessment Specific gravity, measurable by a hygrometer or by commer- of urine volume over a 6 h period was equivalent to hourly as- cially available dry strips also reflects changes in osmolality, sessments for the diagnosis of oliguria and subsequently AKI however their usefulness to diagnose dehydration has been [20]. This is of great importance in the diagnosis of a patient questioned because a dehydrated patient will unlikely start to with oliguria in a remote area, where, apart from the history urinate prior to initiation of rehydration and secondly because and examination, specific gravity and urine output may be all the change in specific gravity will substantially lag behind the that is available for the diagnosis and assessment of AKI. actual change in hydration status [27–29]. Urine color may change according to ingested food (e.g. beet- root will turn the urine red). Turbidity and odor may also be of Point-of-care testing diagnostic value for specific causes of renal dysfunction. The first available POCT methods had a low level of accuracy The first contact between village healthcare providers and and precision, but recent developments demonstrate good trained professionals could initially be telephonic reporting his- agreement between results using currently marketed POCT de- tory, blood pressure measurements or digital transmission of vices and standard laboratory methods [21]. imaging from portable sonography. The most frequently used laboratory method for measuring creatinine is based on the color change induced by the reaction of Urine microscopy creatinine with picric acid in the Jaffe reaction. The presence of Microscopic examination of centrifuged fresh urine for red cells so-called pseudo-chromogens (molecules such as ketones, glucose and polymorphonuclear leucocytes, tubular cells, and red cell and bilirubin in the plasma reacting with the picric acid) reduce and tubular cell casts may be of value for the diagnosis of non- the accuracy of this method. Newer enzymatic methods eliminate AKI causes of oliguria such as glomerular or interstitial diseases, this problem [30] and have permitted the development of smaller infection or obstruction (see below [21]). Urine microscopy is a devices useable at the bedside [30] without any problems con- useful diagnostic tool in every context of renal disease, with a ferred by the pseudo-chromogens in the plasma. However, it is of remarkable specificity as shown in a recent assessment of its note that these methods are generally more costly, which is re- diagnostic accuracy [22] and a recently developed urinary sedi- flected in the price for each measurement (Table 4). ment scoring system diagnosing based on the number of renal POCT devices not only allow the assessment of serum cre- tubular epithelial cells and granular casts has shown to be able atinine for AKI diagnosis but may also be helpful to diagnose to predict worsening of AKI during hospitalization [23]. electrolyte derangements such as increases in serum potas- However, diagnoses made based on microscopy not only re- sium. Serial measurements with a POCT may be of particular quire the tool per se but also highly specialized training, which value to monitor AKI patients. Other parameters measurable Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Diagnosis of AKI in low-income countries | 15 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 4. POCT devices for serum creatinine Device Manufacturer Sample type Sample volume Consumable Supply storage Dimensions (width  Power Time to Price Price per test temperature length  height); result portability and weight i-STAT Abbott Whole blood 65 mL Cartridge 6–8 C 7.7  23.5  7.2 cm; hand- AC or battery 2 min 15 000– 15–20 USD held, 0.7 kg 20 000 USD Stat Sensor Nova Whole blood, ca- 1 mL Dry strip 4–8 C 15.3  8.3  4.6 cm; hand- AC or battery 0.5 min 3995 USD 6 USD Biomedical pillary blood held, 0.4 kg LabGeo-PT10 Smart Samsung Whole blood 70 mL Cartridge n/a 140  205  206 mm, hand- AC or battery 7 min 8000 USD 15–20 USD Blood Analyzer held, 2.0 kg IRMA TRUpoint ITC Whole blood, ca- 200 mL or 125 mLin Cartridge 2–8 C 29.2  24.1  12.7 cm; port- AC or battery 1 min 8–10 000 10–15 USD pillary blood capillary collection able, 2.4 kg USD kit Reflotron Roche Whole blood, 30 mL Dry strip n/a 21  30  35 cm; benchtop AC, optional 2–3 min 6500 USD 4–5 USD serum, plasma but portable, 5 kg battery operation Piccolo xpress Abraxis Whole blood, 9 mL Self-contained 2–8 C 32.4  15.2  20.3 cm; AC or battery 12 min 18 000 USD 20 USD serum or multi-analyte benchtop, 5 kg plasma reagent disc Spotchem EZ Arkray Whole blood, 250 mL Dry strip <30 C 33.8  20  16.3; benchtop; AC or battery 8–15 min 8500 USD  6 USD serum or 5.5 kg plasma Prices are estimates based on research results online at various distributors in the USA and Europe and may vary by region, vendor, etc. These estimates only have the purpose to approximate the costs associated with the purchase and use and are by no means replacing a cost estimate by a vendor. 16 | J.G. Raimann et al. with POCTs range from general chemistry measurements (elec- Non-handheld devices trolytes, glucose, urea nitrogen, blood gases) to enzymes such LabGeo-PT10 Smart Blood Analyzer as glutamate pyruvate transaminase (GPT), gamma-glutamyl The LabGeo PT10 by Samsung is a device weighing about 2 kg transferase (GGT), glutamic oxaloacetic transaminase (GOT) and that does require electrical power supply (AC 100  240 V/50 creatine phosphokinase (CPK). Due to considerably higher costs, 60 Hz). The device operates between 15 C and 32 C. Application these latter methods are not widely used. of whole blood is on a dry test cartridge (not requiring cooling), which, by application of pressure via a plunger, separates cells from plasma, and measures creatinine as one of the analyses Handheld devices on two different multi-analyte cartridges. It delivers a creatinine Abbott iStat (handheld) reading within 7 min. In a recent comparison, the LabGeo PT10 The hand held, battery-operated (two 9 V alkaline lithium bat- showed good reproducibility and agreement with serum and teries) iStat (Table 4), weighing 0.7 kg, measures creatinine and whole-blood specimen measurements using the Roche Cobas is established as a popular useful device in situations such as 8000 modular analyzer (Roche, Switzerland [36]). disaster relief [16] or radiology units using contrast agents [31]. Measurements require a small cartridge that can be inserted IRMA TRUpoint into the iStat. Within 2 min, the device can measure an entire The IRMA TRUpoint Blood Gas analyzer is portable and weighs panel of laboratories or just creatinine. Although the iStat can approximately 2.4 kg. The device operates at temperatures be- measure substances in plasma and serum samples, the manu- tween 12 C and 30 C and at a humidity not exceeding 80%. Cartridges, designed to measure arterial or venous whole blood facturer recommends the use of whole blood for creatinine (or alternatively capillary blood when collected with a lithium- (iStat Manual ART: 714446-00H, REV. DATE 17 February 2011). heparin-containing capillary collection device supplied by the The limitations include that cartridges need to be stored be- manufacturer), need to be stored between 2 C and 8 C and need tween 2 C and 8 C, need a warm-up time of around 10 min and a warm-up time of 15 min. The comparison between the IRMA cannot be cooled again after exposure to ambient temperature. TRUpoint and the Jaffe and enzymatic methods showed that They need to be used within 2 weeks after exposure to tempera- the device results are reproducible: replicate differences of 0.01 tures >8 C. An additional downside is the manufacturer’s rec- (ranging from 0.2 to 0.6) mg/dL and accurate (systematic bias ommendation to not use the device at ambient temperatures of 0.05 mg/dL) and precise (coefficient of variation 6.1%) in >30 C. In terms of accuracy and precision, the iStat overesti- clinical settings. Compared with the reference method the mates creatinine measurements with a systematic bias of IRMA TRUpoint did not show a significant bias [32]. 0.16 mg/dL compared with the Roche Jaffe method, and 0.23 mg/ dL compared with a Roche enzymatic method, respectively [32]. Reflotron Reproducibility of the replicate samples was acceptable with a The Reflotron Plus Chemistry analysis weighs around 5 kg. It coefficient of variation of 3.2% [32]. can optionally be battery-operated (i.e. car battery at 12/24 V DC voltage) and measures creatinine after application of the sam- Nova StatSensor ple (whole blood, plasma or serum) on a dry test strip. The strip The StatSensor (Table 4) is a battery-operated (3.7 V Li polymer separates plasma from whole blood but through a separation rechargeable or replaceable), handheld POCT device measuring pad, which allows a measurement in only 2–3 min. The manu- creatinine; it weighs 0.4 kg. The StatSensor can utilize whole facturer recommends an operational temperature of between blood (arterial and venous) and capillary blood obtained by fin- 15 C and 34 C with a maximum humidity of 90%. A recent ana- gerprick. After the sample is applied on a test strip and inserted lysis showed small bias and good precision (0.12 mg/dL (95% for measurement, it provides a result within 30 s. Similar to the 0.07–0.17) for creatinine levels lower than 5.7 mg/dL and 0.59 iStat, cartridges have to be stored at a temperature between 6 C (0.77 to 0.40) with higher creatinine levels [37]. and 8 C, but the operational temperature is between 15 C and Piccolo xpress 40 C[33]. In a recent study of 100 subjects, venous whole blood The Abraxis Piccolo xpress weighs around 5 kg and can option- samples were measured with the StatSensor and compared ally be battery-operated (i.e. car battery at 15 V DC, 5.0 A). It with an enzymatic creatinine assay as the reference method. measures creatinine in whole blood, serum or plasma after ap- The correlation was good R of 0.93; standard error of the esti- plication to a self-contained multi-analyte reagent disc. The de- mate was 0.22 mg/dL and a negative proportional bias of 30% vice can operate at temperatures between 15 C and 32 C and [34]. When creatinine measurements were performed using a the cartridges are storable for up to 18 months at a temperature fingerprick sample, the results suggest an underestimation of between 2 C and 8 C. Once a disc is removed from refrigeration 0.54 mg/dL compared with the factory setting [35]. (and left unopened) it must be used within a few hours. The A more recent analysis evaluated the performance of the Piccolo xpress uses centrifugation prior to measuring, which slightly smaller and more specific StatSensor Xpress creatinine delays the measurement to 12 min. At the time of this writing analyzer (not available in the USA). It reported good agreement no in-vivo data on creatinine testing was found; however, data compared with a standard laboratory enzymatic method (con- provided by the manufacturer reports minimal bias and accept- cordance correlation coefficient of 0.97 with a systematic bias of able accuracy when compared with reference methods. 0.12; N¼ 60), except at higher creatinine levels, where agree- ment was worse (systematic bias 0.23; N¼ 15 [33]). Blood-based diagnosis summary Another analyzer from the same company is the Stat Profile pHOx Series. However, while some classify it as a POCT device, The above-listed devices were intentionally chosen to include it is not a preferred tool for use in remote settings given its di- only those with a maximal weight of 5 kg. We believe that size mension (30  30  37.5 cm) and weight of 9 kg. and weight are important parameters to determine whether the Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Diagnosis of AKI in low-income countries | 17 device is practical for use in remote settings. The Abbott i-STAT function in the early 20th century [44], and since the 1960s as a useful tool to monitor BUN clearance during hemodialysis [45]. and the Nova StatSensor are hand held devices operated with batteries and their advantage for use in remote villages is clear. More recent efforts have studied SUN with the use of a dip- stick method [46–48], which is already in use in veterinary medi- Others are benchtop devices, weighing up to 5 kg; they are cine. This method measures SUN after sample application on a nevertheless portable (or at the very least, transportable), and test pad containing urease, which cleaves urea to ammonia and seem to be fit for the purpose from the logistic point of view. carbon dioxide, forming ammonium hydroxide. This increases Machines heavier than 5 kg and designed for benchtop use are the pH of the pad as shown by the color change of a pH indica- suitable for secondary or tertiary healthcare settings. As long as tor. This color can then be compared with a standardized block it fit into a car, can be carried and runs on (preferably recharge- corresponding semi-quantitatively to the SUN concentration. able) batteries, the device has a clear advantage in the proposed This method was developed and is manufactured by Integrated application compared with those being used only on benchtop. Biomedical Technology (Elkhart, IN, USA). It has not yet received Although the diagnostic accuracy of the enzymatic methods Food and Drug Administration approval for human use, but has that are being used in the measurement methods of the POCT been studied and validated in 62 subjects suffering from chronic devices are unaffected by pseudo-chromogens and thus are of kidney disease for the diagnosis of elevated BUN [48] and in a uncompromised usability even in cases of hyperbilirubinemia separate study of 44 subjects diagnosed with AKI, for the diag- as found in malaria patients, practicability in terms of storage nosis of AKI severity [47]. SUN levels agree with BUN assess- and transportability of the test strips or cartridges used for ments, but it is insensitive to change and concentrations lower measurement require consideration. The enzymatic methods than 50 mg/dL. This does not affect the value of the method as a used in POCT devices require storage at cool temperature and good discriminator of high versus low levels. In analyses inves- special considerations in terms of cooling and warming up prior tigating the discriminative abilities of the dipstick, the sensitiv- to use. This, in conjunction with their operating temperatures, ity to assess elevated BUN by means of SUN determination was provides logistic and practical challenges. between 0.77 and 0.85, and a specificity between 0.85 and 0.88. The measurement medium is another area of concern. Most In AKI, the dipstick was studied simultaneously with BUN POCT devices measure creatinine (as the only parameter dis- measurements to aid the discrimination of AKI at stage AKIN III cussed) in whole blood (Table 4). The Reflotron Plus and the from AKI at earlier stages with an acceptable performance with Piccolo xpress can measure creatinine in plasma [38], while the an area under the receiver operating characteristic curve of 0.76 manufacturer of the Nova StatSensor and the IRMA TRUpoint, (95% confidence interval 0.61–0.91) [47]. In a subsequent ana- also claim that their device allows the measurement of creatin- lysis, the agreement between SUN and BUN remained consist- ine with collection of capillary blood, which may however, re- ent over a period of 4 days [46]. The ease of use of the technique sult in less precision [39]. is the fact that no needle-stick is required and the low cost of It is important to note that most laboratory routine and ref- the dipstick (<1 USD) are substantial advantages for use in re- erence methods also show biases between each other. The ac- mote areas. Downsides are of course the level of subjectivity curacy of most of the POCT analyzers shows a small positive conferred by the judgment of the color change and the lack of bias compared with the studied reference methods [15, 35, 38, possibility to automatize measurement and data storage (the 39], but with regard to the aforementioned biases of most refer- dipstick needs to be read after 1–2 min—readings after that will ences methods to the ‘gold standard’, these biases of POCT de- be invalid). In summary, more experience is needed with the vices, and their direction and magnitude, may differ compared SUN dipstick, which is in the process of being technically with the reference method used in the local laboratory. This improved. emphasizes the importance of regular confirmatory studies and the necessity to validate the proper use and functionality of the Discussion POCT device (Table 1 [35]). In many countries, the distance to the next healthcare facility may be large and accessibility may be limited. Healthcare pro- Saliva-based biomarker viders in remotely located communities need diagnostic auton- Salivary urea nitrogen omy. These constraints emphasize the importance of diagnostic tools that can be used in these settings. Such tools must be light, BUN accumulates in the blood when renal function decreases. portable and moderately priced, require little maintenance, and Although BUN is a suboptimal biomarker for the diagnosis of AKI be tolerant of temperature and humidity extremes. because its concentration is dependent on non-renal factors in- On the next level (in regional or district healthcare settings), dependent of kidney function (e.g. renal tubular handling, protein more advanced diagnostic tools are essential to establish the se- intake, protein catabolism, liver diseases, gastrointestinal bleed- verity of disease and to decide which cases need referral to ter- ing, volume status and therapy with high-dose steroids) [40], tiary centers for immediate renal replacement therapy. nevertheless it was reported in the Program to Improve Care in We suggest that the optimal AKI diagnostic tool must be Acute Renal Disease study that acute dialysis initiation at a chosen based on the existing infrastructure where the tool will higher level of BUN associates with an increased risk of death [41, be used. One must distinguish between use in a rural village 42]. It may be argued that particularly in developing countries, with few or no trained healthcare workers, where urinary vol- where many patients may potentially suffer from malnutrition ume can be measured in a walk-in clinic and where training due to low protein intake and consequent low baseline BUN, a and maintenance of a portable point-of-care creatinine meas- sudden increase may be particularly worrisome. urement is possible, or a more specialized second and third Urea is equally distributed in the total body water including level health care facility where electrolyte estimations can be exocrine secretions such as saliva, tears and sweat. It has been obtained. known since the 19th century that saliva urea nitrogen (SUN) re- Several considerations are necessary for choosing the right flects BUN [43] and it was first proposed as a marker of renal point-of-care device. 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Clarke W, Frost SJ, Kraus E et al. Renal Function Testing. In: JH Acknowledgments Nichols (ed). Laboratory medicine practice guidelines evidence- No external funding was received. The results presented in based practice for point-of-care testing. Washington D.C, USA: this paper have not been published previously in whole or The National Academy of Clinical Biochemistry part. We would like to thank the Executive Committee of 18. National Confidential Enquiry into Patient Outcome and the ISN s 0by25 Initiative for their review and input to the Death. Acute Kidney Injury: Adding Insult to Injury. London, UK: manuscript. 2009 19. Kellum JA, Sileanu FE, Murugan R et al. Classifying AKI by urine output versus serum creatinine level. J Am Soc Nephrol Conflicts of interest statement 2015; 26: 2231–2238 20. Macedo E, Malhotra R, Claure-Del Granado R et al. Defining None declared. urine output criterion for acute kidney injury in critically ill patients. Nephrol Dial Transplant 2010; 26: 509–515 References 21. Prescott LF, Brodie DE. A simple differential stain for urinary 1. Susantitaphong P, Cruz DN, Cerda J et al. World incidence sediment. Lancet 1964; 2: 940 of AKI: a meta-analysis. Clin J Am Soc Nephrol 2013; 8: 22. Schinstock CA, Semret MH, Wagner SJ et al. Urinalysis is 1482–1493 more specific and urinary neutrophil gelatinase-associated 2. Mehta RL, Cerda J, Burdmann EA et al. International Society lipocalin is more sensitive for early detection of acute kidney of Nephrology’s 0by25 initiative for acute kidney injury (zero injury. Nephrol Dial Transplant 2013; 28: 1175–1185 preventable deaths by 2025): a human rights case for neph- 23. Perazella MA, Coca SG, Hall IE et al. Urine microscopy is rology. Lancet 2015; 385: 2616–2643 associated with severity and worsening of acute kidney 3. Mehta RL, Burdmann EA, Cerda J et al. Recognition and man- injury in hospitalized patients. Clin J Am Soc Nephrol 2010; agement of acute kidney injury in the International Society 5: 402–408 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Diagnosis of AKI in low-income countries | 19 24. Linder E, Grote A, Varjo S et al. On-chip imaging of 36. Jeong TD, Lee W, Chun S et al. Performance evaluation of the Schistosoma haematobium eggs in urine for diagnosis by LABGEO PT10 point-of-care chemistry analyzer. J Lab Med computer vision. PLoS Negl Trop Dis 2013; 7: e2547 Qual Assur 2013; 35: 70–80 37. Schenk PW, Cransberg K, Wolff ED et al. Point-of-care cre- 25. Floege J, Johnson RJ, Feehally J. Comprehensive Clinical atinine testing in children at risk for sudden deterioration of Nephrology. 4th edn. St Louis, MO: Saunders/Elsevier, 2010 renal function. Clin Chem Lab Med 2007; 45: 1536–1541 26. Kavouras SA, Johnson EC, Bougatsas D et al. Validation of a 38. Centre for Evidence-Based Purchasing. 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Blood Purif 2016; 42: 64–72 meter and reagent strip technology for whole blood testing. 47. Calice-Silva V, Vieira MA, Raimann JG et al. Saliva urea nitro- Clin Biochem 2010; 43: 1026–1029 gen dipstick—a novel bedside diagnostic tool for acute kid- 35. Shephard M, Peake M, Corso O et al. Assessment of the Nova ney injury. Clin Nephrol 2014; 82: 358–366 StatSensor whole blood point-of-care creatinine analyzer for 48. Raimann JG, Kirisits W, Gebetsroither E et al. Saliva urea dip- the measurement of kidney function in screening for chronic stick test: application in chronic kidney disease. Clin Nephrol kidney disease. Clin Chem Lab Med 2010; 48: 1113–1119 2011; 76: 23–28 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

International Society of Nephrology’s 0by25 initiative (zero preventable deaths from acute kidney injury by 2025): focus on diagnosis of acute kidney injury in low-income countries

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European Renal Association - European Dialysis and Transplant Association
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© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.
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2048-8505
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Abstract

In developing countries with limited medical infrastructure, preservation and recovery of renal function following acute kidney injury (AKI) is difficult. In conjunction with clinical presentation, rapid measurement of renal function is essential for early diagnosis and management. Especially in low- and middle-income countries, simple interventions such as hydra- tion and avoidance of toxins have the highest probability of recovery. In such contexts, measurement of urine volume and osmolality and serum creatinine with point-of-care devices and saliva urea nitrogen dipsticks can be valuable. This review aims to identify currently available methodologies to assist in reaching the ambitious goal of the 0by25 initiative to elimin- ate all preventable deaths from AKI by 2025. Key words: AKI, biomarkers, blood and saliva urea nitrogen, creatinine, guidelines, intensive care, systematic review Introduction [1, 5], with dehydration and hypotension being the most com- mon cause in recently published data [3]. Acute kidney injury (AKI) is increasingly recognized as a major In LMIC, a large fraction of newly occurring community- public health challenge, particularly in less privileged areas of acquired AKI is due to causes, which have a substantial poten- the world. Despite technological progress and substantial pre- tial of reversibility with simple interventions [2, 5]. Infectious ventive efforts, the incidence of AKI in these countries remains diseases (mainly gastroenteritis associated with diarrhea, mal- high with an estimated 13.3 million cases per year (85% of aria and leptospirosis) and obstetric complications are the lead- which in developing countries), and it was further estimated that around 1.7 million deaths can be attributed to AKI [1–4]. ing causes of AKI, followed by animal venoms and natural herbal medicines [2]. Although treating the underlying cause is Although AKI in developed countries with sophisticated med- of prime importance, death as a consequence of AKI may often ical infrastructure is predominantly a disease found in hospital- ized, elderly and very sick patients, in low- and middle-income be prevented by simple interventions such as oral rehydration countries (LMIC) it is largely a community-acquired condition or immediate temporary dialysis. Given the potential Received: August 17, 2016. Accepted: November 9, 2016 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Diagnosis of AKI in low-income countries | 13 reversibility of AKI with early intervention, early diagnosis is of of devices with a substantially smaller footprint has become particular importance. However, given the possibility of causing possible in remote environments. Some of these POCT devices an even greater risk of adverse outcomes by fluid overloading can be utilized in conjunction with smart phones, which auto- patients where rehydration is not indicated [6], accurate diag- matically digitize results and communicate via text message or nostic tools are central to safely intervene at an early stage. the world-wide-web. These devices are available to measure Provision and utilization of early diagnostic tools in remote biomarkers of a broad range of diseases and can be used in areas without an adequately trained medical and nursing infra- blood, plasma, sweat, urine and saliva specimens. In combin- structure and often lacking power sources is a major deterrent ation with medical history and examination, and routine diag- to change [7, 8]. Even when diagnostic tools and therapeutic de- nostic instruments, point-of-care techniques reveal a wide vices are available, specific training of primary healthcare pro- range of applications and enable care to be delivered to a large viders can be difficult. A detailed review on risk factors, number of patients in LMIC. As current diagnostic measures are management and all associated challenges has recently been based, in part, on the use of serum creatinine (RIFLE [11], AKIN published [9]. [12] and KDIGO Guidelines [13]), measurement of this parameter The International Society of Nephrology’s AKI initiative aims is crucial. to prevent all avoidable death from AKI by 2025 (0by25) [2]. A re- Point-of-care devices have already found use in the monitor- cently conducted and published Global Snapshot study as- ing of the administration of nephrotoxic agents in radiologic sessed during a 10-week period the whole range of AKI as facilities [14], during surgery, to monitor the effects of exposure reported by 322 caregivers from all over the world on 4018 diag- to nephrotoxic drugs in oncology or to dose antibiotics [14, 15]. nosed patients [3]. Currently, pilot projects are being designed Experience with these devices in remote areas without tech- and launched that aim to assess the management of AKI in a nical and medical infrastructure corroborates their usefulness real-life setting in low-income countries and to identify areas of [16]. However, it is imperative that the use of POCT devices in improvement. developing countries needs to be consistent with practices in In the context of the International Society of Nephrology’s the developed world ([17]; Table 1). Furthermore, it is important 0by25 initiative, this report aims to evaluate currently available that POCT devices need to be able to connect to commonly used methods for early diagnosis of AKI in remote areas with inad- data processing devices (i.e. smartphones, tabloids, computers) equate medical infrastructure. in order to transmit or store data for future use, such as clinical observation and monitoring, and/or clinical research. Point-of-care testing Diagnosis of AKI This manuscript will focus on point-of-care testing (POCT) only. Thus, we will not discuss other potential methods of measuring AKI diagnosis is mainly based on changes in urine volume, renal function that are expensive and are not used on a routine plasma creatinine and blood urea nitrogen (BUN). Assessments basis for clinical care, including low molecular weight proteins of urine osmolality (or specific gravity), urinary sodium concen- such as cystatin C, up-regulated proteins such as NGAL, KIM-1, tration and fractional excretion of sodium and urea possibly LFABP and IL-18, and tubular enzymes that are excreted in the have value to diagnose conditions such as dehydration and urine as a results of tubular acute injury. Additionally, a new hypotension (particularly important for developing countries generation of biomarkers useful in the diagnosis of AKI, the cell where these conditions are the most common cause of AKI). cycle arrest biomarkers, require mentioning and are currently Current KDIGO recommendations (Table 2) have found broad under intensive research will not be discussed in this manu- acceptance [13]. However, the need for blood draws and urine script [10]. collection is generally difficult in remote villages. The development of new generation diagnostic devices and Herein, we briefly discuss clinical presentation, and urine-, biomarkers has widened the available methodologies needed to blood- and saliva-based biomarkers of interest for the diagnosis make early diagnosis outside of hospitals. However, their use and assessment of severity of AKI. demands the development of a new infrastructure to operate the devices and communicate results. Some diagnostic elem- Clinical presentation and medical history ents, such as urine dipsticks, remain available and are invalu- able for screening purposes or in the detection of suspected The clinical history is essential in the diagnosis of AKI, usually disease. Finally, with the advancement of technology and preceded by infection-related vomiting and diarrhea leading to strong consumer support of the ‘smaller is better’ concept, use dehydration and hypovolemia, or ingestion of drugs (including Table 1. Practice recommendations of the American Association for Clinical Chemistry and the National Academy for Clinical Biochemistry on the use of point-of-care technology devices Development and maintenance of a comprehensive quality assurance program, including operator training and competency assessment, quality control, equipment maintenance, reagent storage, periodic correlation of results with a central laboratory and troubleshooting of sig- nificant discrepancies or errors. An interdisciplinary work group including physicians and laboratory professionals. Close collaboration between the laboratory director and POCT users to monitor testing and to investigate deviations, complaints or incidents is essential. Training programs and continuing education of those involved on dissemination of knowledge of recent innovations and limitations in POCT devices and testing. Data management as a mechanism to improve the quality of POCT. Concurrent central laboratory creatinine testing of the same samples is recommended for the early stages of program development and conduct of regular quality assurance studies. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 14 | J.G. Raimann et al. Table 2. KDIGO: definition and classification of AKI Table 3. Pathophysiological correlates of urine discoloration (based on [20]) AKI Serum creatinine Urine output stage Pink Hematuria, hemoglobinuria and myoglobinuria; massive uric acid crystalluria 1 1.5–1.9 times baseline <0.5 mL/kg/h for Red Hematuria, hemoglobinuria and myoglobinuria; OR 6–12 h porphyrinuria and alkaptonuria (turns black on 0.3 mg/dL (26.5 mmol/L) increase standing) 2 2.0–2.9 times baseline <0.5 mL/kg/h for Brown Hematuria, hemoglobinuria and myoglobinuria; 12 h jaundice 3 3.0 times baseline <0.3 mL/kg/h for Black Hematuria, hemoglobinuria and myoglobinuria OR 24 h White (milky) Chyluria Increase in serum creatinine to OR Velvet Urinary infection (certain strains of Escherichia coli) 4.0 mg/dL (353.6 mmol/L) Anuria for 12 h OR Initiation of renal replacement therapy does render these diagnostic methods less practical in remote OR settings. It may, however, be envisioned that future techno- In patients <18 years, decrease in logical innovations such as one allowing the imaging of hel- eGFR to<35 mL/min/1.73 m minth eggs using mini-microscopes constructed from webcams Known or presumed to have occurred during the prior 7 days. and mobile phone cameras [24] will one day allow for affordable Within the preceding 48 h. urinary microscopy in remote settings in developing countries. eGFR, estimated glomerular filtration rate. It may further be envisioned that more sophisticated approaches, possibly with electronic transfer of images or auto- mated methods of diagnosis, could at one point enable the rou- tine use of urinary microscopy in medically isolated settings. herbal medicines), snake bites, parasitic diseases such as mal- aria, obstetric complications and other etiologies. Often, the clinical presentation is dominated by the underlying disease Urine osmolality/specific gravity and the AKI-specific symptoms are lost within a myriad of Reports of changes in frequency of urination and urinary vol- disease-specific symptoms [4, 18]. ume and color provide valuable information (see Table 3;[25]) Oliguria is not always present in AKI, but when present pro- and it is well established that dehydration causes increases in vides valuable information. KDIGO guidelines define a reduction serum and urine osmolality. Work using the diagnostic value of of urine volume as an independent criterion for AKI diagnosis color scales to diagnose urinary osmolality and possible dehy- (Table 2). It has been reported that mortality is highest when dration deserves mentioning in this context [26]. Measurement both creatinine elevation and oliguria are present [19]. A recent of urinary osmolality requires an osmometer or a refractometer. publication in critically ill patients showed that an assessment Specific gravity, measurable by a hygrometer or by commer- of urine volume over a 6 h period was equivalent to hourly as- cially available dry strips also reflects changes in osmolality, sessments for the diagnosis of oliguria and subsequently AKI however their usefulness to diagnose dehydration has been [20]. This is of great importance in the diagnosis of a patient questioned because a dehydrated patient will unlikely start to with oliguria in a remote area, where, apart from the history urinate prior to initiation of rehydration and secondly because and examination, specific gravity and urine output may be all the change in specific gravity will substantially lag behind the that is available for the diagnosis and assessment of AKI. actual change in hydration status [27–29]. Urine color may change according to ingested food (e.g. beet- root will turn the urine red). Turbidity and odor may also be of Point-of-care testing diagnostic value for specific causes of renal dysfunction. The first available POCT methods had a low level of accuracy The first contact between village healthcare providers and and precision, but recent developments demonstrate good trained professionals could initially be telephonic reporting his- agreement between results using currently marketed POCT de- tory, blood pressure measurements or digital transmission of vices and standard laboratory methods [21]. imaging from portable sonography. The most frequently used laboratory method for measuring creatinine is based on the color change induced by the reaction of Urine microscopy creatinine with picric acid in the Jaffe reaction. The presence of Microscopic examination of centrifuged fresh urine for red cells so-called pseudo-chromogens (molecules such as ketones, glucose and polymorphonuclear leucocytes, tubular cells, and red cell and bilirubin in the plasma reacting with the picric acid) reduce and tubular cell casts may be of value for the diagnosis of non- the accuracy of this method. Newer enzymatic methods eliminate AKI causes of oliguria such as glomerular or interstitial diseases, this problem [30] and have permitted the development of smaller infection or obstruction (see below [21]). Urine microscopy is a devices useable at the bedside [30] without any problems con- useful diagnostic tool in every context of renal disease, with a ferred by the pseudo-chromogens in the plasma. However, it is of remarkable specificity as shown in a recent assessment of its note that these methods are generally more costly, which is re- diagnostic accuracy [22] and a recently developed urinary sedi- flected in the price for each measurement (Table 4). ment scoring system diagnosing based on the number of renal POCT devices not only allow the assessment of serum cre- tubular epithelial cells and granular casts has shown to be able atinine for AKI diagnosis but may also be helpful to diagnose to predict worsening of AKI during hospitalization [23]. electrolyte derangements such as increases in serum potas- However, diagnoses made based on microscopy not only re- sium. Serial measurements with a POCT may be of particular quire the tool per se but also highly specialized training, which value to monitor AKI patients. Other parameters measurable Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Diagnosis of AKI in low-income countries | 15 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 4. POCT devices for serum creatinine Device Manufacturer Sample type Sample volume Consumable Supply storage Dimensions (width  Power Time to Price Price per test temperature length  height); result portability and weight i-STAT Abbott Whole blood 65 mL Cartridge 6–8 C 7.7  23.5  7.2 cm; hand- AC or battery 2 min 15 000– 15–20 USD held, 0.7 kg 20 000 USD Stat Sensor Nova Whole blood, ca- 1 mL Dry strip 4–8 C 15.3  8.3  4.6 cm; hand- AC or battery 0.5 min 3995 USD 6 USD Biomedical pillary blood held, 0.4 kg LabGeo-PT10 Smart Samsung Whole blood 70 mL Cartridge n/a 140  205  206 mm, hand- AC or battery 7 min 8000 USD 15–20 USD Blood Analyzer held, 2.0 kg IRMA TRUpoint ITC Whole blood, ca- 200 mL or 125 mLin Cartridge 2–8 C 29.2  24.1  12.7 cm; port- AC or battery 1 min 8–10 000 10–15 USD pillary blood capillary collection able, 2.4 kg USD kit Reflotron Roche Whole blood, 30 mL Dry strip n/a 21  30  35 cm; benchtop AC, optional 2–3 min 6500 USD 4–5 USD serum, plasma but portable, 5 kg battery operation Piccolo xpress Abraxis Whole blood, 9 mL Self-contained 2–8 C 32.4  15.2  20.3 cm; AC or battery 12 min 18 000 USD 20 USD serum or multi-analyte benchtop, 5 kg plasma reagent disc Spotchem EZ Arkray Whole blood, 250 mL Dry strip <30 C 33.8  20  16.3; benchtop; AC or battery 8–15 min 8500 USD  6 USD serum or 5.5 kg plasma Prices are estimates based on research results online at various distributors in the USA and Europe and may vary by region, vendor, etc. These estimates only have the purpose to approximate the costs associated with the purchase and use and are by no means replacing a cost estimate by a vendor. 16 | J.G. Raimann et al. with POCTs range from general chemistry measurements (elec- Non-handheld devices trolytes, glucose, urea nitrogen, blood gases) to enzymes such LabGeo-PT10 Smart Blood Analyzer as glutamate pyruvate transaminase (GPT), gamma-glutamyl The LabGeo PT10 by Samsung is a device weighing about 2 kg transferase (GGT), glutamic oxaloacetic transaminase (GOT) and that does require electrical power supply (AC 100  240 V/50 creatine phosphokinase (CPK). Due to considerably higher costs, 60 Hz). The device operates between 15 C and 32 C. Application these latter methods are not widely used. of whole blood is on a dry test cartridge (not requiring cooling), which, by application of pressure via a plunger, separates cells from plasma, and measures creatinine as one of the analyses Handheld devices on two different multi-analyte cartridges. It delivers a creatinine Abbott iStat (handheld) reading within 7 min. In a recent comparison, the LabGeo PT10 The hand held, battery-operated (two 9 V alkaline lithium bat- showed good reproducibility and agreement with serum and teries) iStat (Table 4), weighing 0.7 kg, measures creatinine and whole-blood specimen measurements using the Roche Cobas is established as a popular useful device in situations such as 8000 modular analyzer (Roche, Switzerland [36]). disaster relief [16] or radiology units using contrast agents [31]. Measurements require a small cartridge that can be inserted IRMA TRUpoint into the iStat. Within 2 min, the device can measure an entire The IRMA TRUpoint Blood Gas analyzer is portable and weighs panel of laboratories or just creatinine. Although the iStat can approximately 2.4 kg. The device operates at temperatures be- measure substances in plasma and serum samples, the manu- tween 12 C and 30 C and at a humidity not exceeding 80%. Cartridges, designed to measure arterial or venous whole blood facturer recommends the use of whole blood for creatinine (or alternatively capillary blood when collected with a lithium- (iStat Manual ART: 714446-00H, REV. DATE 17 February 2011). heparin-containing capillary collection device supplied by the The limitations include that cartridges need to be stored be- manufacturer), need to be stored between 2 C and 8 C and need tween 2 C and 8 C, need a warm-up time of around 10 min and a warm-up time of 15 min. The comparison between the IRMA cannot be cooled again after exposure to ambient temperature. TRUpoint and the Jaffe and enzymatic methods showed that They need to be used within 2 weeks after exposure to tempera- the device results are reproducible: replicate differences of 0.01 tures >8 C. An additional downside is the manufacturer’s rec- (ranging from 0.2 to 0.6) mg/dL and accurate (systematic bias ommendation to not use the device at ambient temperatures of 0.05 mg/dL) and precise (coefficient of variation 6.1%) in >30 C. In terms of accuracy and precision, the iStat overesti- clinical settings. Compared with the reference method the mates creatinine measurements with a systematic bias of IRMA TRUpoint did not show a significant bias [32]. 0.16 mg/dL compared with the Roche Jaffe method, and 0.23 mg/ dL compared with a Roche enzymatic method, respectively [32]. Reflotron Reproducibility of the replicate samples was acceptable with a The Reflotron Plus Chemistry analysis weighs around 5 kg. It coefficient of variation of 3.2% [32]. can optionally be battery-operated (i.e. car battery at 12/24 V DC voltage) and measures creatinine after application of the sam- Nova StatSensor ple (whole blood, plasma or serum) on a dry test strip. The strip The StatSensor (Table 4) is a battery-operated (3.7 V Li polymer separates plasma from whole blood but through a separation rechargeable or replaceable), handheld POCT device measuring pad, which allows a measurement in only 2–3 min. The manu- creatinine; it weighs 0.4 kg. The StatSensor can utilize whole facturer recommends an operational temperature of between blood (arterial and venous) and capillary blood obtained by fin- 15 C and 34 C with a maximum humidity of 90%. A recent ana- gerprick. After the sample is applied on a test strip and inserted lysis showed small bias and good precision (0.12 mg/dL (95% for measurement, it provides a result within 30 s. Similar to the 0.07–0.17) for creatinine levels lower than 5.7 mg/dL and 0.59 iStat, cartridges have to be stored at a temperature between 6 C (0.77 to 0.40) with higher creatinine levels [37]. and 8 C, but the operational temperature is between 15 C and Piccolo xpress 40 C[33]. In a recent study of 100 subjects, venous whole blood The Abraxis Piccolo xpress weighs around 5 kg and can option- samples were measured with the StatSensor and compared ally be battery-operated (i.e. car battery at 15 V DC, 5.0 A). It with an enzymatic creatinine assay as the reference method. measures creatinine in whole blood, serum or plasma after ap- The correlation was good R of 0.93; standard error of the esti- plication to a self-contained multi-analyte reagent disc. The de- mate was 0.22 mg/dL and a negative proportional bias of 30% vice can operate at temperatures between 15 C and 32 C and [34]. When creatinine measurements were performed using a the cartridges are storable for up to 18 months at a temperature fingerprick sample, the results suggest an underestimation of between 2 C and 8 C. Once a disc is removed from refrigeration 0.54 mg/dL compared with the factory setting [35]. (and left unopened) it must be used within a few hours. The A more recent analysis evaluated the performance of the Piccolo xpress uses centrifugation prior to measuring, which slightly smaller and more specific StatSensor Xpress creatinine delays the measurement to 12 min. At the time of this writing analyzer (not available in the USA). It reported good agreement no in-vivo data on creatinine testing was found; however, data compared with a standard laboratory enzymatic method (con- provided by the manufacturer reports minimal bias and accept- cordance correlation coefficient of 0.97 with a systematic bias of able accuracy when compared with reference methods. 0.12; N¼ 60), except at higher creatinine levels, where agree- ment was worse (systematic bias 0.23; N¼ 15 [33]). Blood-based diagnosis summary Another analyzer from the same company is the Stat Profile pHOx Series. However, while some classify it as a POCT device, The above-listed devices were intentionally chosen to include it is not a preferred tool for use in remote settings given its di- only those with a maximal weight of 5 kg. We believe that size mension (30  30  37.5 cm) and weight of 9 kg. and weight are important parameters to determine whether the Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Diagnosis of AKI in low-income countries | 17 device is practical for use in remote settings. The Abbott i-STAT function in the early 20th century [44], and since the 1960s as a useful tool to monitor BUN clearance during hemodialysis [45]. and the Nova StatSensor are hand held devices operated with batteries and their advantage for use in remote villages is clear. More recent efforts have studied SUN with the use of a dip- stick method [46–48], which is already in use in veterinary medi- Others are benchtop devices, weighing up to 5 kg; they are cine. This method measures SUN after sample application on a nevertheless portable (or at the very least, transportable), and test pad containing urease, which cleaves urea to ammonia and seem to be fit for the purpose from the logistic point of view. carbon dioxide, forming ammonium hydroxide. This increases Machines heavier than 5 kg and designed for benchtop use are the pH of the pad as shown by the color change of a pH indica- suitable for secondary or tertiary healthcare settings. As long as tor. This color can then be compared with a standardized block it fit into a car, can be carried and runs on (preferably recharge- corresponding semi-quantitatively to the SUN concentration. able) batteries, the device has a clear advantage in the proposed This method was developed and is manufactured by Integrated application compared with those being used only on benchtop. Biomedical Technology (Elkhart, IN, USA). It has not yet received Although the diagnostic accuracy of the enzymatic methods Food and Drug Administration approval for human use, but has that are being used in the measurement methods of the POCT been studied and validated in 62 subjects suffering from chronic devices are unaffected by pseudo-chromogens and thus are of kidney disease for the diagnosis of elevated BUN [48] and in a uncompromised usability even in cases of hyperbilirubinemia separate study of 44 subjects diagnosed with AKI, for the diag- as found in malaria patients, practicability in terms of storage nosis of AKI severity [47]. SUN levels agree with BUN assess- and transportability of the test strips or cartridges used for ments, but it is insensitive to change and concentrations lower measurement require consideration. The enzymatic methods than 50 mg/dL. This does not affect the value of the method as a used in POCT devices require storage at cool temperature and good discriminator of high versus low levels. In analyses inves- special considerations in terms of cooling and warming up prior tigating the discriminative abilities of the dipstick, the sensitiv- to use. This, in conjunction with their operating temperatures, ity to assess elevated BUN by means of SUN determination was provides logistic and practical challenges. between 0.77 and 0.85, and a specificity between 0.85 and 0.88. The measurement medium is another area of concern. Most In AKI, the dipstick was studied simultaneously with BUN POCT devices measure creatinine (as the only parameter dis- measurements to aid the discrimination of AKI at stage AKIN III cussed) in whole blood (Table 4). The Reflotron Plus and the from AKI at earlier stages with an acceptable performance with Piccolo xpress can measure creatinine in plasma [38], while the an area under the receiver operating characteristic curve of 0.76 manufacturer of the Nova StatSensor and the IRMA TRUpoint, (95% confidence interval 0.61–0.91) [47]. In a subsequent ana- also claim that their device allows the measurement of creatin- lysis, the agreement between SUN and BUN remained consist- ine with collection of capillary blood, which may however, re- ent over a period of 4 days [46]. The ease of use of the technique sult in less precision [39]. is the fact that no needle-stick is required and the low cost of It is important to note that most laboratory routine and ref- the dipstick (<1 USD) are substantial advantages for use in re- erence methods also show biases between each other. The ac- mote areas. Downsides are of course the level of subjectivity curacy of most of the POCT analyzers shows a small positive conferred by the judgment of the color change and the lack of bias compared with the studied reference methods [15, 35, 38, possibility to automatize measurement and data storage (the 39], but with regard to the aforementioned biases of most refer- dipstick needs to be read after 1–2 min—readings after that will ences methods to the ‘gold standard’, these biases of POCT de- be invalid). In summary, more experience is needed with the vices, and their direction and magnitude, may differ compared SUN dipstick, which is in the process of being technically with the reference method used in the local laboratory. This improved. emphasizes the importance of regular confirmatory studies and the necessity to validate the proper use and functionality of the Discussion POCT device (Table 1 [35]). In many countries, the distance to the next healthcare facility may be large and accessibility may be limited. Healthcare pro- Saliva-based biomarker viders in remotely located communities need diagnostic auton- Salivary urea nitrogen omy. These constraints emphasize the importance of diagnostic tools that can be used in these settings. Such tools must be light, BUN accumulates in the blood when renal function decreases. portable and moderately priced, require little maintenance, and Although BUN is a suboptimal biomarker for the diagnosis of AKI be tolerant of temperature and humidity extremes. because its concentration is dependent on non-renal factors in- On the next level (in regional or district healthcare settings), dependent of kidney function (e.g. renal tubular handling, protein more advanced diagnostic tools are essential to establish the se- intake, protein catabolism, liver diseases, gastrointestinal bleed- verity of disease and to decide which cases need referral to ter- ing, volume status and therapy with high-dose steroids) [40], tiary centers for immediate renal replacement therapy. nevertheless it was reported in the Program to Improve Care in We suggest that the optimal AKI diagnostic tool must be Acute Renal Disease study that acute dialysis initiation at a chosen based on the existing infrastructure where the tool will higher level of BUN associates with an increased risk of death [41, be used. One must distinguish between use in a rural village 42]. It may be argued that particularly in developing countries, with few or no trained healthcare workers, where urinary vol- where many patients may potentially suffer from malnutrition ume can be measured in a walk-in clinic and where training due to low protein intake and consequent low baseline BUN, a and maintenance of a portable point-of-care creatinine meas- sudden increase may be particularly worrisome. urement is possible, or a more specialized second and third Urea is equally distributed in the total body water including level health care facility where electrolyte estimations can be exocrine secretions such as saliva, tears and sweat. It has been obtained. known since the 19th century that saliva urea nitrogen (SUN) re- Several considerations are necessary for choosing the right flects BUN [43] and it was first proposed as a marker of renal point-of-care device. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/12/2999357 by Ed 'DeepDyve' Gillespie user on 16 March 2018 18 | J.G. Raimann et al. First, some of the currently available point-of-care devices to of Nephrology 0by25 Global Snapshot: a multinational cross- measure creatinine (Table 4) have the disadvantage of needing sectional study. Lancet 2016; 387: 2017–2025 power supply. SUN assessment may be useful to overcome this 4. Lewington AJ, Cerda J, Mehta RL. Raising awareness of acute limitation and to allow measurements in limited settings. kidney injury: a global perspective of a silent killer. Kidney Int Second, most devices require that cartridges be stored in a 2013; 84: 457–467 cool environment and once the cooling chain is broken, the 5. Cerda J, Bagga A, Kher V et al. The contrasting characteristics cartridges must be used within a defined period of time. This of acute kidney injury in developed and developing coun- implies the need for electricity or solar power for refrigeration. tries. Nat Clin Pract Nephrol 2008; 4: 138–153 At the village level or in a remote rural area, a simple tool 6. Maitland K, Kiguli S, Opoka RO et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med such as a urine dipstick detecting an ongoing pathological renal process may aid the decision to call and organize costly transport 2011; 364: 2483–2495 7. Callegari JG, Kilonzo KG, Yeates KE et al. Peritoneal dialysis to a higher specialized facility. Confirmation of AKI by POCT de- vices would be ideal to confirm initial dipstick tests suggestive of for acute kidney injury in sub-Saharan Africa: challenges faced and lessons learned at Kilimanjaro Christian Medical AKI. One may envision the use of a simple technique such as the SUN dipstick in the rural villages in conjunction with the more Centre. Kidney Int 2012; 81: 331–333 8. Carter M, Kilonzo K, Odiit A et al. Acute peritoneal dialysis accurate POCT devices (at higher levels of healthcare). The SUN dipstick would there serve, in combination with what is learned treatment programs for countries of the east African com- munity. Blood Purif 2012; 33: 149–152 from anamnesis and clinical presentation, to maximize the infor- mation gain to accurately diagnose AKI. 9. Ponce D, Balbi A. Acute kidney injury: risk factors and man- agement challenges in developing countries. Int J Nephrol Cost efficiency is an important consideration in the context Renovasc Dis 2016; 9: 193–200 of diagnosis of AKI in developing countries. Although POCT de- 10. Kashani K, Al-Khafaji A, Ardiles T et al. Discovery and valid- vices have the ability to determine serum creatinine at costs be- ation of cell cycle arrest biomarkers in human acute kidney tween 4000 and 20 000 USD, other approaches cost substantially less. In particularly, SUN dipsticks costing <1 USD require men- injury. Crit Care 2013; 17: R25 11. Bellomo R, Ronco C, Kellum JA et al. Acute renal failure— tioning in this context. This is in sharp contrast to the cost of a measurement using a POCT device, where every single test runs definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International at around 4–20 USD (and additionally requires refrigeration, which causes additional costs). Considering a child with sus- Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204–R212 pected AKI requiring frequent assessments or a child diagnosed AKI where management is being monitored using a POCT de- 12. Mehta RL, Kellum JA, Shah SV et al. Acute kidney injury net- work: report of an initiative to improve outcomes in acute vice, this would quickly accumulate substantial costs. Diagnostic is of immense importance for our endeavors to kidney injury. 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Clinical Kidney JournalOxford University Press

Published: Feb 1, 2018

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