Posted: March 12th, 2023

journal

(1) Read'' Acute kidney injury: Challenges and opportunities "article then the two additional articles ( Challenges of targeting vascular stability in acute kidney injury & The importance of early detection in stopping acute kidney injury)

2. After you've read the 3 articles (attached) provide an un plagiarized summation of at least 500 words. Include all 3 references. Use APA format throughout the document.

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Acute kidney injury: Challenges and opportunities

BY NHAN L.A. DINH, MSN, CNP, AGACNP-BC, CCRN

Abstract: Acute kidney injury (AKI) can be a devastating diagnosis for any patient and can increase mortality during hospitalization. There can be long-term consequences for those who survive the initial insult. This article discusses AKI and its implications for nurses.

Keywords: acute kidney injury, Acute Kidney Injury Network, AKI, chronic kidney disease, CKD, community-acquired acute kidney injury, hospital-acquired acute kidney injury, KDIGO, Kidney Disease Improving Global Outcomes, Nephrotoxic Injury Negated by Just-in-time Action, sick day rule

ACUTE KIDNEY INJURY (AKI) is a heterogeneous kidney disorder that increases in-hospital morbidity and mortality. In 2016 data, the inci- dence of AKI was 20% for Medicare patients with both chronic kidney disease (CKD) and diabetes.1 Based on Veterans Affairs (VA) 2016 data, AKI occurred in more than 25% of hospitalized veterans over age 22, but less than 50% of those with lab-documented AKI were coded as such.1 The chief concern here is a missed opportunity for intervention. AKI increases long-term risk of CKD, but if clinicians do not recognize the diagnosis, they cannot follow up or intervene. An AKI diagnosis also increases the chance of another AKI episode, with a 30% risk of a recur- rent AKI episode within 1 year.

Mortality is increased with an AKI episode. Medicare data from 2016

shows in-hospital mortality of 8.2%, but this increases to over 13% when including patients who were dis- charged to hospice.1 The in- hospital mortality for patients without AKI was only 1.8% (3.8% if including patients discharged to hospice).1 Pa- tients with AKI also were more likely to be referred to a long-term-care facility. (See Hospital discharge status of first hospitalization for Medicare patients ages 66+, 2016.)

AKI defined AKI was previously known as acute renal failure.

However, many pa- tients with kidney injury did not progress to renal failure, yet still had significant, often permanent, loss of kidney function. Researchers worked to better define AKI and noted that it is a potential but often reversible rapid deterioration of kidney func-

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tion, with or without kidney dam- age. It may or may not be associated with oliguria.

Numerous groups attempted to define AKI from both a clinical and physiologic point of view to allow for epidemiologic studies. A consensus group developed the first criteria with a definition relying on changes in the serum creatinine (SCr), glo- merular filtration rate (GFR), and/or urine output, known as Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage kid- ney disease (RIFLE).3 The Acute Kid- ney Injury Network (AKIN) believed RIFLE mixed outcomes with severity classes and developed another classi- fication, the AKIN criteria.4 In 2012, Kidney Disease: Improving Global Outcomes (KDIGO), an international organization, standardized the com- peting definitions of AKI (RIFLE and AKIN) into one coherent classifica- tion.2 (See Classifications of AKI.)

Using this chart and per interna- tional KDIGO consensus criteria, AKI is diagnosed when there is an increase in SCr from baseline by at least 0.3 mg/dL within 48 hours

or an increase in SCr to at least 1.5 times from baseline known or pre- sumed to have occurred within the 7 days before AKI diagnosis.2 The guidelines also specify that the di- agnosis can be made when there is a urine volume of less than 0.5 mL/ kg/h for 6 hours.2

AKI can be divided into two cat- egories: community-acquired AKI (CA-AKI) and hospital-acquired AKI (HA-AKI). Patients who present to a hospital meeting criteria for AKI as listed above are defined as having CA-AKI.5 HA-AKI has been the focus of research over the last 2 decades as rates of AKI have steadily increased and continue to do so.6 However, CA-AKI has gained more attention recently because of its prevalence; it was recently stated that nearly 50% of AKI incidents begin in the com- munity setting.7,8,10 This statistic is concerning and healthcare providers need to be alert to patients in their practice who are at risk. In 2013, the International Society of Nephrology launched the “0by25” initiative as a global target to ensure zero death of patients with preventable and treatable AKI by 2025 while raising

awareness to change incidence and prognosis worldwide.9 One difficulty with tracking CA-AKI is that it is easier to obtain records and statistics on hospitalized patients, but CA-AKI is often treated outpatient. CA-AKI can be prevented and treated.10 It is crucial for healthcare professionals to promptly identify patients with CA- AKI as well as those who are at risk for developing CA-AKI.

Etiology of AKI and risk factors for CA-AKI AKI is caused by endogenous and/ or exogenous conditions, including but not limited to severe ischemia or sepsis, dehydration, gastrointestinal (GI) bleeding, anemia, and/or use of nephrotoxic agents.11-13 These causes are often multifactorial. For example, patients with sepsis are given renal- toxic doses of antibiotics.

Etiology of AKI can be divided into three categories: prerenal, intrarenal/ intrinsic kidney disease, and postrenal. (See AKI etiologies.) Prerenal causes, such as volume depletion from de- hydration, GI losses (vomiting, diar- rhea, bleeding), excessive diuresis, hemorrhage from trauma, and/or

Hospital discharge status of first hospitalization for Medicare patients ages 66+, 20161

49.1

8.2

7.6

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5.0

68.8 1.8

4.7

22.7

2.0

Home

Death

Other

Institution

Hospice

With AKI diagnosis Without AKI diagnosis

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changes in vascular resistance occur- ring from disease processes or certain drug use, cause hypoperfusion to the kidneys.11-13 These changes, in turn, lead to a lower GFR.

Intrarenal AKI can result from a prolonged prerenal state with or without toxic insults related to toxins, drugs, or any underlying systemic process such as sepsis. Inflammation and ischemia of the kidneys can be sequelae of those insults.12,13 Over-the-counter (OTC) and prescribed medications are a common intrarenal cause of CA- AKI. Examples include nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management, angiotensin- converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) for hypertension and CKD with diabetes, proton pump inhibi- tors for gastric reflux, and cyclospo- rine and/or tacrolimus for antirejec- tion management.12,13

Intrarenal AKI

can be categorized by the compo- nents of the kidney that are primarily affected: tubular, glomerular, intersti- tial, and vascular.12,13

Postrenal AKI, the least common etiology, is usually caused by an obstruction in urinary flow out of either a single kidney or both kid- neys. In postrenal AKI, kidneys still produce urine, but the urine cannot be excreted via the urethra due to blockage. Therefore, the urine backs

Classifications of AKI2-4

Stage Urine Output RIFLE*

Intrarenal AKI can result from a prolonged prerenal state with or without toxic insults related to drugs or

an underlying systemic process.

up into the kidneys (retrograde flow), impairing renal functions. Obstruction of urinary flow can result from obstructing stones or blood clots in the ureters or renal pelvises, an enlarged prostate, dys-

AKIN

function or obstruction of the blad- der, and/or strictures in the urinary system.12,13

Volume depletion is more com- monly the cause of CA-AKI than HA-AKI.14 Incidence of AKI increas- es during summer months, when the risk of dehydration is greater. Two studies found that pre-renal causes relating to AKI are almost two-fold higher than all other causes together.5,14

Patients are at the highest risk for CA-AKI when they have significant comorbidities along with polyphar- macy.15 Diuretics are associated with a higher incidence of CA-AKI than ACE inhibitors and ARBs.6 A combi- nation of these medications puts pa- tients at a greater risk for developing CA-AKI than diuretics alone.

Even though risk factors for CA- AKI and HA-AKI are similar, CA-AKI is common in older adult males with comorbidities including diabetes mellitus, hypertension, heart disease, CKD, cancer, and/or dementia.1,6,14

Gender also plays a role in CA-AKI development. Men across all age groups are at higher risk for CA-AKI compared with their female coun- terparts. This factor is thought to be mediated in part by testosterone.16,17

According to a Vanderbilt University study, testosterone has been found to increase renal GFR expression, which is associated with the likelihood of

KDIGO

25% baseline or ≥0.3 mg/dL baseline or ≥0.3 mg/dL

50% baseline

3 3x base- for 24 h or or decrease in GFR >75% SCr of ≥4 mg/dL (with acute line or increase in SCr ≥ 4.0 anuria for 12 h rise of ≥0.5 mg/dL) mg/dL or initiation of renal

replacement therapy

* Loss and ESRD of the RIFLE criteria are not included in this staging chart, as they are considered outcome variables.

Used with permission from Erica Davis, PA-C: AAPA presentation. 2017. New Orleans, La.

www.Nursing2020.com September l Nursing2020 l 47

progressive kidney injury.17 The exact mechanism remains unclear and is currently being investigated. Further, Black, Hispanic, and hospitalized patients with a previous diagnosis of AKI are more likely to develop AKI than those from different ethnic groups or those without risk fac- tors.1,6,14,16,18

As noted previously, patients with diabetes mellitus and CKD tend to have more incidents of AKI than those without comorbidities.1 Al- though CKD has consistently been shown to increase risk for the devel- opment of AKI, one study found that it does not pose any significant dif- ferences in the severity of AKI.14

Signs and symptoms of AKI Although the kidneys are responsible for regulating extracellular and in- travascular fluid volume, osmolality, electrolyte concentrations, pH, and excretion of wastes and toxins in the body, AKI does not manifest any specific signs and symptoms until

AKI etiologies Prerenal AKI

other organs or systems are affected. Patients with AKI can present with either oliguria or nonoliguria. Signs and symptoms of AKI also depend on the causes that dictate how rapid and severe the decline of kidney function is.11-13 Most patients pre- senting to a hospital with AKI are not aware that they have this condition. Patients often present with signs and symptoms that later cause AKI (such as hemorrhage or severe nausea and vomiting) or signs and symptoms related to complications of AKI (in- cluding altered mental status, severe edema, shortness of breath, malaise/ lethargy, hemodynamic instability, and dysrhythmias). These signs and symptoms are often related to uremia or its underlying causes.11-13

AKI management AKI management depends on the underlying etiology and the severity of kidney injury. Because mortal- ity is high in patients with AKI, the most important goal of therapy is

Intrarenal AKI

preventing life-threatening compli- cations.11-13 However, current AKI interventions are limited to support- ive care and prevention of causative factors. Any possible causes of AKI and its contributing factors should be prevented, treated, or removed as soon as possible.11,12

Prevention and early detection are the keys to improving outcomes for patients with AKI. For example, ACE inhibitors and ARBs should be held temporarily in patients with decreased oral intake and in those who present with prerenal AKI that may have started in the community setting, because these drugs may exacerbate a prerenal state. While waiting for the kidneys to recover on their own, restricting or avoid- ing substances and medications that are known to impair kidney func- tion is vital. In the event of signifi- cant electrolyte derangement and/ or fluid overload, emergent dialysis can be performed to prevent further complications related to cardiac dys-

Postrenal AKI

↓ Intravascular volume Acute tubular necrosis Upper urinary tract obstruction • Dehydration/hemorrhage • Ischemic: • Intrinsic • GI, cutaneous, or renal losses – Sepsis – Stone • Third spacing – Hypotension – Papillary necrosis

• Nephrotoxic: – Blood clot ↓ Effective blood volume – Drugs – Tumor • Heart failure – Heme pigments • Extrinsic • Cirrhosis – Retroperitoneal fibrosis • Nephrotic syndrome Acute interstitial nephritis – Malignancy • Sepsis • Drug-induced – Ligation • Anesthesia • Infection-related – Pelvic mass

• Systemic diseases Altered renal hemodynamics • Malignancy Lower urinary tract tract obstruction • Preglomerular constriction • Urethral stricture • Postglomerular vasodilation Acute glomerulonephritis • Benign prostatic hyperplasia • Medications: ACE inhibitors, NSAIDs • Prostate cancer • Hepatorenal syndrome, surgery Acute vascular syndrome • Bladder cancer

• Renal artery dissection • Bladder stones Renal vascular obstruction • Renal artery thromboembolism • Neurogenic bladder

• Renal vein thrombosis • Malpositioned indwelling urinary Abdominal compartment syndrome • Atheroembolic disease catheter

Used with permission from Catherine Wells, DNP: NKF presentation. 2013. Orlando, Fla.

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rhythmias, heart failure, or respira- tory failure during hospitalization. Collaboration among the interdisci- plinary team, including primary care physicians, hospitalists, nephrolo- gists, nurses, and advanced practice providers, is crucial in optimizing AKI management.

CA-AKI outcomes CA-AKI has been identified as the most common type of AKI.14 CA- AKI accounted for almost 80% of the patients with a discharge diagnosis of AKI at a single VA hospital, and its severity was found to be as significant as HA-AKI.14 If present at admission, CA-AKI has a significant impact on hospital length of stay and is associ- ated with a substantially higher risk of death and CKD progression.14,19

The rate of rehospitalization in pa- tients with CA-AKI versus HA-AKI did not differ, and early temporary dialysis may improve the outcome of CA-AKI.10,18 However, those who initially present with CA-AKI exhibit the highest incidence of CKD at their 5-year follow-up.19 Two studies found that 40.2% of patients developed CKD stage 3 (GFR 30 to 60 mL/min) or higher, and nearly 27% progressed to either CKD stage 5 (GFR less than 15 mL/min) or end-stage renal dis- ease (ESRD) requiring dialysis.19

CA-AKI is often underappreciated as a clinic or office-based issue.14,20

In patients presenting with upper re- spiratory or GI complaints, clinicians may focus on the presenting condition and may not consider dehydration and the need to adjust certain medica- tions. In addition, many patients pres- ent to urgent care and are treated for the problem and labs are not checked for existing kidney disease.

Some patients self-medicate with OTC combination or multisymptom medications containing NSAIDs, such as naproxen or ibuprofen. This compounds the chance of develop- ing AKI. The National Kidney Foun- dation has a patient website that

An AKI diagnosis increases the chance

of another AKI episode, with a 30% risk of

recurrence within 1 year.

highlights medication dosing for the at-risk patient.21

Prevention Multiple studies have shown an im- provement of outcomes in patients with AKI with early detection as well as preventive measures when AKI is diagnosed.8,10,14,16,22 Stress to patients in the community setting the im- portance of optimization of volume status as well as avoiding exposures to any nephrotoxic agents.10 When primary prevention fails to prevent AKI from occurring, the Recognition- Action-Result framework can act as a secondary prevention by properly diagnosing and evaluating AKI with a goal of limiting duration and severity to prevent complications.10

A multidisciplinary approach has been recommended for tertiary pre- vention of AKI. This includes close

monitoring, medication review, and reassessment of patients, especially those with a history of AKI.2,10,12

Outpatient preventive measures after the first episode of AKI are vital in improving quality of life, alleviating long-term complications, and limit- ing recurrences.

One of the most promising preventive methods is implement- ing “sick day rules” developed by the National Health Service of the United Kingdom.23 Sick is defined as vomiting or diarrhea (unless minor), fevers, sweats, and shaking. When these symptoms occur, patients are directed to temporarily stop taking: • NSAIDs, which can impair re- nal autoregulation by inhibiting prostaglandin-mediated vasodilation of the afferent arterioles and may increase the risk of AKI. • ACE inhibitors and ARBs, which reduce systemic BP and also cause vasodilation of the efferent arterioles, further reducing glomerular perfu- sion pressure. • Diuretics (including spironolactone and eplerenone), which can cause hypovolemia and AKI. • Other BP-lowering medications. • Medications that may accumulate due to decreased kidney function caused by hypotension, increasing the risk of adverse reactions. Ex- amples include metformin (risk of lactic acidosis), sulfonylureas (risk of hypoglycemia), and trimethoprim (risk of hyperkalemia).

Screening for children at risk Because AKI can be especially dev- astating in children, researchers at Cincinnati Children’s Hospital (CCH) developed an electronic health record screening and trigger program for the hospital.24 Enrolling all non-critically ill hospitalized children between 2011 and 2015, CCH decreased the exposure rate of nephrotoxic medica- tions by 38%. More important, CCH reduced the incidence of AKI by an impressive 64%.24

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www.Nursing2020.com https://hospital.24 https://Kingdom.23 https://complications.10 https://agents.10 https://patient.21 https://dialysis.19 https://follow-up.19 https://HA-AKI.14 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

CCH reports the most impor- tant aspect of the program was the person-person interaction. If the pharmacist noted three or more nephrotoxic medications for one patient, he or she would notify the healthcare team. The pharmacist would highlight the risk and discuss other medications that would be less nephrotoxic, but leave the final deci- sion to the healthcare team.24 CCH offered this software application and clinical system to all children’s hospitals nationwide, and more than 14 children’s hospitals have imple- mented it.25

Implications for nurses Because CA-AKI and HA-AKI can both be devastating diagnoses for any patient, nurses must be familiar with the pathophysiology of AKI in order to promptly recognize signs and symptoms. Early treatment is the key to preventing further complica- tions and progression of AKI. For example, nurses in a primary care setting should implement the “sick day rules” to help reduce the risks of CA-AKI development. In the case of AKI trajectory, it is important for the nurse to educate the patient about the acute condition and supportive care for kidney recovery. Nephrology referral is beneficial for follow-up in the event of worsening of AKI or CKD development.

Timely intervention is key AKI is associated with significant clinical consequences and increased healthcare costs. It is crucial that all providers identify patients at risk for AKI and conduct primary prevention. Preventive measures are especially im- portant in high-risk patients, includ- ing those with previous AKI exposure, CKD, older age, or other high-risk comorbidities.

When AKI is present, diagnosis must be made in a timely manner to allow for prompt management. The process of minimizing progression

of AKI, especially with CA-AKI, is important both at hospital admission and at the clinic or office visit.

Though awareness of CA-AKI has increased recently, it is still an under- appreciated clinical presentation. Further research should focus more on comprehensive risk assessment, biomarkers, and management for HA-AKI and CA-AKI to ensure high- quality care.26 Preventive measures can be provided at the community level to patients with a previous AKI diagnosis and patients who may be at risk for developing AKI.2,10 ■

REFERENCES

1. United States Renal Data System. 2018 USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2018.

2. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1-138.

3. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group Crit Care. 2004;8(4):R204-R212.

4. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31.

5. Schissler MM, Zaidi S, Kumar H, Deo D, Brier ME, McLeish KR. Characteristics and outcomes in community-acquired versus hospital-acquired acute kidney injury. Nephrology (Carlton). 2013;18(3):183-187.

6. Stucker F, Ponte B, De la Fuente V, et al. Risk factors for community-acquired acute kidney injury in patients with and without chronic kidney injury and impact of its initial management on prognosis: a prospective observational study. BMC Nephrol. 2017;18(1):380.

7. Jha V, Parameswaran S. Community-acquired acute kidney injury in tropical countries. Nat Rev Nephrol. 2013;9(5):278-290.

8. Sawhney S, Fluck N, Fraser SD, et al. KDIGO- based acute kidney injury criteria operate differently in hospitals and the community- findings from a large population cohort. Nephrol Dial Transplant. 2016;31(6):922-929.

9. International Society of Nephrology. AKI-0by25. 2020. www.theisn.org/all-articles/616-0by25.

10. Kashani K, Rosner MH, Haase M, et al. Quality improvement goals for acute kidney injury. Clin J Am Soc Nephrol. 2019;14(6):941-953.

11. American Nephrology Nurses Association. Core Curriculum for Nephrology Nursing: Acute Kidney Injury. 6th ed. Pitman, NJ: American Nephrology Nurses Association; 2015.

12. Gilbert SJ, Weiner DE, Bomback AS, Perazella MA, Tonelli M. National Kidney Foundations Primer on Kidney Diseases. 7th ed. Philadelphia, PA: Elsevier; 2018.

13. Lerma E, Sparks M, Topff J. Nephrology Secrets. 4th ed. Philadelphia, PA: Elsevier; 2019.

14. Wang Y, Wang J, Su T, Qu Z, Zhao M, Yang L. Community-acquired acute kidney injury: a nationwide survey in China. Am J Kidney Dis. 2017;69(5):647-657.

15. Mesropian PD, Othersen J, Mason D, Wang J, Asif A, Mathew RO. Community-acquired acute kidney injury: a challenge and opportunity for primary care in kidney health. Nephrology (Carlton). 2016;21(9):729-735.

16. Holmes J, Geen J, Phillips B, Williams JD, Phillips AO, Welsh AKI Steering Group. Community acquired acute kidney injury: findings from a large population cohort. QJM. 2017;110(11):741-746.

17. Zhang MZ, Sasaki K, Li Y, et al. The role of the EGF receptor in sex differences in kidney injury. J Am Soc Nephrol. 2019;30(9):1659-1673.

18. Moreno-Gonzalez G, Perez-Fernandez X, Cardenas-Campos P, et al. Community acquired vs. hospital acquired acute kidney injury. Mortality and timing of renal replacement therapy. Intensive Care Med Exp. 2015;3(suppl 1):A257.

19. Soto K, Campos P, Pinto I, et al. The risk of chronic kidney disease and mortality are increased after community-acquired acute kidney injury. Kidney Int. 2016;90(5):1090-1099.

20. Wonnacott A, Meran S, Amphlett B, Talabani B, Phillips A. Epidemiology and outcomes in community-acquired versus hospital-acquired AKI. Clin J Am Soc Nephrol. 2014;9(6):1007-1014.

21. National Kidney Foundation. 5 drugs you may need to avoid or adjust if you have kidney disease. 2019. www.kidney.org/atoz/content/5-drugs-you- may-need-avoid-or-adjust-if-you-have-kidney- disease.

22. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1-150.

23. National Health Service. “Sick day” guidance in patients at risk of acute kidney injury: a position statement from the Think Kidneys Board. Version 9: January 2018. www.thinkkidneys.nhs.uk/aki/wp- content/uploads/sites/2/2018/01/Think-Kidneys- Sick-Day-Guidance-2018 .

24. Goldstein SL, Mottes T, Simpson K, et al. A sustained quality improvement program reduces nephrotoxic medication-associated acute kidney injury. Kidney Int. 2016;90(1):212-221.

25. Cincinnati Children’s. NINJA system aims to reduce acute kidney injury in hospitalized kids nationwide. 2017. www.cincinnatichildrens.org/ research/divisions/b/bmi/news/2017/3-02-ninja- system-poised-to-reduce-acute-kidney-injuries-in- hospitalized-kids-nationwide.

26. Kwong YD, Liu KD. Prediction models for AKI: will they result in improved outcomes for AKI? Clin J Am Soc Nephrol. 2019;14(4):488-490.

Nhan L.A. Dinh is a certified nurse practitioner at University of New Mexico Hospital in Albuquerque, N.M.

The author has disclosed no financial relationships related to this article.

This article originally appeared as Dinh NLA. Acute kidney injury: challenges and opportunities. Nurse Pract. 2020;45(4):48-54.

DOI-10.1097/01.NURSE.0000694776.10448.97

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www.Nursing2020.com https://DOI-10.1097/01.NURSE.0000694776.10448.97 www.cincinnatichildrens.org www.thinkkidneys.nhs.uk/aki/wp www.kidney.org/atoz/content/5-drugs-you www.theisn.org/all-articles/616-0by25

JULY 2017 M L O - O N L I N E .C O M 38

FUTURE BUZZ ACU T E K IDNE Y INJURY

The importance of early detection in stopping acute kidney injury By Salvatore Di Somma, MD

A cute kidney injury (AKI) is as serious and common as a heart attack, and it can strike without any warning signs or symptoms. It affects as many one in fi ve hospital pa-

tients in the United States1 and can rapidly develop into chronic kidney disease (CKD) or kidney failure, leading in more severe cases to the need for permanent dialysis treatment with com- promised quality of life or even to death. Sometimes called a silent killer, AKI is often overlooked as the true cause of mortal- ity. AKI is also one of the costliest health issues both in the U.S. and around the world.

Compounding the problem is that the medical community has been slow to recognize the disease and implement a stan- dard of care. However, recent developments and research have led to new testing that can detect AKI much earlier than other commonly used tests and is expected to improve clinical and economic outcomes for patients and hospitals.

What is AKI? AKI is the rapid deterioration of kidney function within hours or days. It is often diagnosed in the context of other acute ill- nesses.2 It indicates initial subclinical kidney cell injury that can be reversible if the condition is detected early, before dysfunc- tion. AKI is most commonly brought on by an infl ux of drugs or toxins or contrast-induced substances, a blockage of urine, serious infection, trauma, acute heart failure, major surgery, or chronic illness. Up to 50 percent of critically ill patients will develop some stage of AKI.3 Patients most at risk are those in intensive care, as well as the elderly and diabetic patients.

AKI can cause the accumulation of waste products, electro- lytes, and fl uid in the body as well as reduced immunity and dysfunction of other organs.2 Prevention through proper test- ing is the best measure to address AKI. Treatment of AKI can include many different therapeutic strategies such as reducing the intake of antibiotics or other drugs, managing fl uids and diuretic dosages, and monitoring urine output. Other treat- ments or surgeries could be delayed until the kidneys are functioning normally. If detection of the risks of AKI occurs early enough and changes to treatment are made, the kid- neys can sometimes normalize themselves; consequently, it is crucial to immediately recognize all phases of AKI occurrence.

More cases, more costs While AKI is a preventable disease, it is a growing problem around the world. A 2014 report by the National Confi den- tial Enquiry into Patient Outcome and Death (NCEPOD), a London-based nonprofi t that reviews the management of pa- tients through research and surveys, found that 30 percent of AKI cases that occurred during hospital admission were avoid- able. The same report established that only 50 percent of pa- tients with AKI received an overall standard of care considered good. Rates for AKI and mortality in ICU patients with AKI are quite similar across the continents. Current strategies to reduce AKI in developed countries have been found to be ineffective or have not been adequately implemented. It is also remarkable that the different levels of healthcare systems across the conti- nents, from the most to the least advanced, do not infl uence the mortality rate of AKI.

AKI has been known to the medical community for at least the past century. Over the past two decades, however, the avail- ability of electronic health records and large cohorts of patients with AKI have made studying the disease in different settings possible. Studies show that both the number of cases and the severity of the disease have been increasing. People are living longer, so there are more patients at risk of developing AKI worldwide, particularly those with chronic conditions and those undergoing major surgery. As a result, there have been rapid increases in the incidence of AKI reported, highlighting a growing impact on the public health burden of advanced kidney disease in the U.S. and beyond. In fact, a 2014 study published in Kidney International showed that AKI occurs in 18 percent of all general hospitalizations and up to 50 percent of all ICU cases worldwide.4 AKI cases requiring dialysis have also become more prevalent.4

The mortality rate of hospitalized patients with AKI is remaining steady, continuing to be high at about 50 percent.5 In the U.S. alone, AKI is responsible for two million deaths per year6 and $10 billion in costs to the healthcare system.7 The later AKI is detected, the greater the associated costs. For pa- tients, AKI can lead to longer hospital stays and higher hospi- tal bills, particularly when they are referred to chronic dialy- sis treatment. As a consequence, for hospitals detecting AKI early is critical to improving care and patient outcomes and reducing costs.

Despite the disease’s prevalence and severity, AKI awareness among patients and those in the medical community, including doctors and hospital administrators, is still relatively low. AKI has been identifi ed by different methodologies, and there was no standardization of care until 2012, when the global nonprofi t Kidney Disease Improving Global Outcomes (KDIGO), dedi- cated to improving the care and outcomes of kidney disease patients around the world, created the KDIGO Clinical Practice Guidelines for Acute Kidney Injury. This development has con- tributed to more widespread discussion and awareness about the disease.

Testing is the answer Addressing both the clinical and economic concerns related to AKI requires prevention by early detection and treatment of patients at risk for developing the disease. Since 1917, the way to test for AKI has been by serum creatinine (SCr). Today, AKI is still most commonly detected by SCr and urine output tests, based on RIFLE (Risk, Injury, Failure, Loss of kidney func- tion, and End-stage kidney disease), AKIN (Acute Kidney In- jury Network), or KDIGO methods. The problem with using SCr for detection of AKI, however, is that the diagnosis comes too late. The time required to detect a rise in SCr as a conse- quence of kidney damage is 24 to 48 hours, and during this pe- riod of initial renal cellular damage, before SCr rises, almost 50 percent of kidney function can be lost.8 Serum creatinine lev- els also can be abnormal due to factors that are not related to kidney function, since it is coming as degradation of muscle cells, and from the liver, independent of kidney function.

The SCr and urine output tests measure the function of the kidney, so it should be noted that these tests detect

continued on page 40

MLO201707_FutureBuzz-Ortho_MECH_AL.indd 38MLO201707_FutureBuzz-Ortho_MECH_AL.indd 38 6/12/2017 11:11:29 AM6/12/2017 11:11:29 AM

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FUTURE BUZZ ACU T E K IDNE Y INJURY

Salvatore Di Somma, MD, serves as

Director Emergency Medicine, Faculty

Medicine and Psychology, Sapienza

University of Rome, Sant’Andrea

Hospital Rome. He is also an Associ-

ate Professor of Medicine, Faculty of

Medicine and Psychology, Sapienza

University of Rome, Department of

Medical-Surgery Sciences and Translational Medicine,

and Chairman Postgraduate School of Emergency

Medicine, Faculty of Medicine and Psychology,

Sapienza University of Rome.

dysfunction, not injury. Because of this, the medical community has been able to diagnose the disease only after the kidney has been damaged and there is already a higher risk of mortality. The goal should be to identify patients who are suffering an injury, so clinicians can intervene and remove the cause of the injury before it causes dysfunction.

One assay that recently became commercially available in the U.S. and Europe detects injury before the loss of function. It is a urine test that provides lab results in 16 minutes, allow- ing clinicians to assess the risk of AKI and proactively inter- vene before damage occurs. While SCr is a fi ltration function marker, the new test measures the TIMP2 and IGFBP7 proteins that are upregulated in response to cellular/tissue injury. Com- pared to SCr, the new test is more sensitive, accurate, and, most important, faster in indicating AKI.

Biomarkers are traditionally identifi ed through theoretical discovery but are often proven not to have viable applications in a clinical setting. The discovery of the TIMP2 and IGFBP7 biomarkers was different in that it was the result of a dedicated study created to identify and validate new biomarkers of AKI. The study isolated a group of more than 522 critically ill adults in three distinct cohorts—including patients with sepsis, shock, trauma, and major surgery—and a comparison group, and ex- amined more than 300 biomarkers. As a result, the two novel biomarkers, the TIMP2 and IGFBP7, were clinically validated as the best indicators of patients at risk for AKI.

All healthcare professionals need to know that AKI is detect- able and preventable. Incorporating best practices and new methods for testing for AKI should be part of any quality care protocol. Improving the clinical and economic outcomes of AKI begins with detection.

REFERENCES

1. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. Kidney Inter., Suppl. 2012;2:1-138.1. 2. Ostermann M, Joannidas M. Acute kidney injury 2016: diagnosis and diagnostic workup. Crit Care. 2016;20:299. 3. Mandelbaum T, Scott D, Lee J, et al. Outcome of critically ill patients with acute kidney injury using the AKIN Criteria. Crit Care Med. 2011;39(12)2659-2664. 4. Siew ED, Davenport A. The growth of acute kidney injury: a rising tide or just closer attention to details? Kidney Int. 2015;87(1):46–61. 5. Ympa YP, Skar Y, Reinhart K, Vincent JL. Has mortality from acute renal failure de- creased? A systematic review of the literature. Am J Med. 2005;118(8):827-832. 6. Ali T, Khan I, Simpson W, et al. Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol. 2007;18(4):1292-1298. 7. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney in- jury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005:16:3365-3370. 8. Ramanathan L. Acute Kidney Injury Risk Assessment, Challenges and Opportunities. Ortho on Demand. 2015.

continued from page 38

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Reproduced with permission of copyright owner. Further reproduction prohibited without permission.

Kidney International (2008) 74 257

commentar yhttp://www.kidney-international.org

The compromise of renal microvascular structure has received considerable atten- tion as a central and possibly causative feature of the development of chronic fibrotic kidney diseases. The reduction in capillary number has been reported in a number of chronic diseases and has been suggested to promote fibrosis in a variety of different ways, including the exacerbation of hypoxia.1,2 However, in the case of chronic kidney disease, the reduction of renal microvessels repre- sents a chicken-and-egg dilemma: does microvessel dropout contribute to renal fibrosis, or does developing renal fibro- sis impinge on renal capillary stability? The answer to this is not known, but data derived from acute or subtle injury mod- els (folate, ischemia, nephrotoxin, tran- sient angiotensin II) demonstrate a loss of capillaries that typically precedes the development of prominent fibrosis.3–5

These observations suggest that pres- ervation or reversal of microvascular loss in a reversible injury model represents a sound strategy for ameliorating the

Challenges of targeting vascular stability in acute kidney injury David P. Basile1

Acute kidney injury following folate administration is characterized by a vascular remodeling that is initially proliferative but subsequently results in vascular endothelial loss. Interventions directed toward promoting endothelial growth may preserve vascular structure and therefore renal function. However, angiopoietin-1 therapy in the setting of folate-induced acute kidney injury resulted in an expanded fibrotic response despite apparent preservation of the vasculature, indicating that renal repair responses are complex and vascular-directed therapies should be approached with caution. Kidney International (2008) 74, 257–258. doi:10.1038/ki.2008.243

development of renal interstitial fibrosis, as well as addressing the role of vascular dropout as an antecedent event in pro- gressing disease. We and others have dem- onstrated that a number of factors with potential to influence vascular growth are altered in the early course of renal injury (in our experience using ischemia/reper- fusion) and have argued that replacement or enhancement of these factors should maintain blood vessel structure and influ- ence long-term outcome.1,6,7

Angiopoietin-1 is a potent angiogenic factor that interacts with the Tie-2 recep- tor on endothelial cells. Angiopoietin-1 has little or no proliferative potential but is a potent inhibitor of endothelial apop- tosis.8 Angiopoietin-1 has promigratory effects on endothelial cells, and this may relate to its important activity facilitat- ing tube formation during angiogenesis. Angiopoietin-1 stimulation also tightens endothelial junctions to reduce vascular leakiness, and this activity may be related to its anti-inflammatory effects. In general, angiopoietin-1 is considered a prominent vascular stabilizing factor in the develop- ment of new blood vessels. Although the effects of angiopoietin-1 are complicated by the sometimes antagonistic activity of the related protein angiopoietin-2, the activities suggest that angiopoietin-1 is ideally suited as a molecule with potential to preserve blood vessels therapeutically.8

The regenerating kidney after an acute insult provides an opportunity to intervene at a potentially critical window of time in which remodeling events may influence vascular integrity and affect long-term function. Angiopoietin-1 expression is increased in a model of acute kidney injury induced by folate administration9 and recently was also shown to be increased in a model of ischemic acute kidney injury.7 It is reasonable to hypothesize that such alterations in expression may represent an attempt to preserve the renal vascula- ture undergoing active injury. It could be suggested that further enhancement of angiopoietin-1 would enhance vascular preservation following acute injury. As it turns out, it also represents an invitation for unanticipated complications.

Long et al.10 (this issue) have sought to address the potential therapeutic role of angiopoietin-1 using adenoviral delivery of a modified human angiopoietin-1 in a mouse model of folate-induced acute kid- ney injury. This model is typically associ- ated with an early (2–3 days) proliferation of cortical capillary endothelial cells fol- lowed by a gradual regression of these cap- illaries at longer times during recovery.9 It was hypothesized that angiopoietin-1 delivery may prevent the regression of capillaries in this model. This indeed was the case. Interestingly, the investigators also observed the simultaneous enhance- ment of interstitial fibrosis characterized by collagen deposition and increased inflammatory-cell deposition.10

Although the authors may have antici- pated different results, the implications of these findings are profound and impactful among those who are interested in vascu- lar repair processes and their potential to affect kidney function. The study should raise considerable awareness of the com- plicated nature of renal repair character- ized by a complex milieu of cell types and altered chemical signaling. It forces atten- tion to the fact that although angiogenesis may be observed in cultures in response to a given trophic factor, in vivo these molecules are promiscuous and may be highly inflammatory depending on the specific setting. It reminds us that renal injury has a prominent inflammatory

1Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA Correspondence: David P. Basile, Department of Cellular & Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA. E-mail: dpbasile@iupui.edu

see original article on page 300

http://www.kidney-international.org mailto:dpbasile@iupui.edu

258 Kidney International (2008) 74

commentar y

component that cannot be overlooked in the evaluation of potential interventions.

Importantly, angiopoietin-1 did, appar- ently, preserve vascular integrity as would be predicted, but the added inflammatory activity is contradictory to its generally observed anti-inflammatory activity. The reason for this may represent an interesting area of future investigation. However, there is evidence that angiopoietin-1 may activate a cascade of inflammatory cytokines.11

In addition, the results should high- light that therapy geared toward vascular preservation or repair may not be ubiqui- tously applied across pathophysiological conditions. Clearly, as the authors noted,10 there has already been considerable atten- tion paid to the potential utility of vascu- lar endothelial growth factor-A, which is protective to blood vessels and prevents further fibrosis in several, but not all, models investigated.12–14 In the case of angiopoietins, a novel and potent form, termed COMP-angiopoietin-1, has been shown to be effective in limiting fibrosis in a model of ureteral obstruction.15 How- ever, as Long et al. point out,10 factors such as the establishment of an effective dose and the form of angiopoietin-1 adminis- tered may also play an important role in outcome. The point of emphasis is that not all conditions are alike, and several other factors may influence vascular stability in disease models. One molecule is not likely to represent a panacea promoting vascular preservation without complications.

Several other questions are brought to mind in consideration of this area of investigation. The first question is whether therapy that targets the vasculature rep- resents a useful approach at all, and if so, what is the basis for deciding what path- ways should be targeted. Although vessel density is clearly compromised and asso- ciated with hypoxia,1 vascular rarefaction does not occur as the sole and isolated event after injury with the potential to complicate chronic kidney function. Recent studies from our laboratory demonstrated that the manifestation of salt-sensitive hypertension and profound secondary chronic kidney disease was essentially nullified by admin- istration of mycophenolate mofetil after the establishment of vascular injury induced by ischemia/reperfusion in rats.16 We interpret these results to suggest that both hypoxia

occurring secondary to vascular loss and a complexity of infiltrating cells are required for the development of fulminant disease and that any of these may represent useful therapeutic targets.

If, as we believe, targeting the vasculature is important, the choice of molecules to be tested may require more specific informa- tion regarding the nature of vascular drop- out. For example, a more global perspective on the alterations of vasculotrophic fac- tors in specific models is required, and therapies should use combinations of factors to compensate for alterations in the angiogenic milieu of the injured kid- ney. Secondly, and related to the previous point, additional knowledge of the likely mechanism by which endothelial cells are lost would be helpful. Curiously, very little is known of the cellular events that lead to the loss of capillary endothelial cells in the setting of acute injury. Although an obvious hypothesis is that endothelial cells undergo apoptosis, aside from a sepsis model there is little direct evidence to sup- port this contention.

As a final point of consideration, we would like to bring attention to the meth- odology used by Long et al.10 to establish preserved vessel density in response to angiopoietin-1 treatment. These investi- gators used CD31 immunohistochemistry to beautiful ly demonstrate that angiopoietin-1- exposed animals have a preserved or enhanced vasculature. This technique is well established, and we have used this approach in our own work. Nev- ertheless, in light of the interesting, unex- pected, and paradoxical results, perhaps further analysis is warranted. Because ves- sels exist to support the perfusion needs of the organ, the physiological efficacy of these preserved vessels should be evaluated more thoroughly. In addition, given that there exist several populations of CD31- positive circulating cells, including many that also express markers of monocyte or macrophage lineage, it is possible that the deposition of such cells, which may be termed ‘angiogenic macrophages,’17 could result in an enhanced inflammatory state masquerading as an angiogenic response.

Regardless, this interesting study high- lights the promise and limitations of targeting the vasculature. In so doing, it defines important obstacles and allows us

to generate new and testable paradigms to mitigate this perplexing problem. DISCLOSURE The authors declared no competing interests.

REfEREnCES 1. Basile DP. The endothelial cell in ischemic acute

kidney injury: implications for acute and chronic function. Kidney Int 2007; 72: 151–156.

2. Norman J, Fine LG. Intrarenal oxygenation in chronic renal failure. Clin Exp Pharmacol Physiol 2006; 33: 989–996.

3. Yuan H-T, Li X-Z, Pitera JE et al. Peritubular capillary loss after mouse acute nephrotoxicity correlates with down-regulation of vascular endothelial growth factor-A and hypoxia-inducible factor-1 alpha. Am J Pathol 2003; 163: 2289–2301.

4. Lombardi D, Gordon KL, Polinsky P et al. Salt- sensitive hypertension develops after short-term exposure to angiotensin II. Hypertension 1999; 33: 1013–1019.

5. Basile DP, Donohoe DL, Roethe K et al. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol 2001; 281: F887–F899.

6. Basile DP, Fredrich K, Chelladurai B et al. Renal ischemia reperfusion inhibits VEGF expression and induces ADAMTS-1, a novel VEGF inhibitor. Am J Physiol Renal Physiol 2008; 294: F928–F936.

7. Horbelt M, Lee S, Mang H et al. Acute and chronic microvascular alterations in a mouse model of ischemic acute kidney injury. Am J Physiol Renal Physiol 2007; 293: F688–F695.

8. Brindle N, Saharinen P, Alitalo K. Signaling and functions of angiopoietin-1 in vascular protection. Circ Res 2006; 98: 1014–1023.

9. Long DA, Woolf AS, Suda T, Yuan HT. Increased renal angiopoietin-1 expression in folic acid-induced nephrotoxicity in mice. J Am Soc Nephrol 2001; 12: 2721–2731.

10. Long DA, Price KL, Ioffe E et al. Angiopoietin-1 therapy enhances fibrosis and inflammation following folic acid-induced acute renal injury. Kidney Int 2008; 74: 300–309.

11. Aplin A, Gelati M, Fogel E et al. Angiopoietin-1 and vascular endothelial growth factor induce expression of inflammatory cytokines before angiogenesis. Physiol Genomics 2006; 27: 20–28.

12. Long D, Mu W, Price K et al. Vascular endothelial growth factor administration does not improve microvascular disease in the salt-dependent phase of post angiotensin II hypertension. Am J Physiol 2006; 291: F1248–F1254.

13. Kang DH, Hughes J, Mazzali M et al. Impaired angiogenesis in the remnant kidney model. II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol 2001; 12: 1448–1457.

14. Kang DH, Anderson S, Kim YG et al. Impaired angiogenesis in the aging kidney: vascular endothelial growth factor and thrombospondin-1 in renal disease. Am J Kidney Dis 2001; 37: 601–611.

15. Kim W, Moon S, Lee S. COMP-angiopoietin-1 ameliorates renal fibrosis in a unilateral ureteral obstruction model. J Am Soc Nephrol 2006; 17: 2474–2483.

16. Pechman KR, Basile DP, Lund H, Mattson DL. Immune suppression blocks sodium-sensitive hypertension following recovery from ischemic acute renal failure. Am J Physiol Regul Integr Comp Physiol 2008; 294: R1234–R1239.

17. Ingram DA, Caplice NM, Yoder MC. Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells. Blood 2005; 106: 1525–1531.

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