Introduction: problem in critical illness. Approximately 5–6% of

   Introduction: Acute kidneyinjury (AKI) is a significant problem in critical illness. Approximately 5–6%of all hospitalized adults and 10% of children suffer from varying degrees ofAKI 1. The presence of AKI in critical illness occurs at a rate of 10–15% andcarries a 50% mortality rate in children requiring dialysis 2,3,4. IncreasingAKI severity, characterized by serum creatinine (SCr)- and urine output(UOP)-based stratifications of AKI, is associated with increased mortality inadults5 and children.6 Notably, small increases in SCr (0.

3 mg/dl) mayreflect significant kidney damage and is associated with poor patient outcomes7,8.Consistently effective AKI therapy to prevent or limit the diseaseintensity is lacking, potentially due to delayed recognition of existing and/orongoing injury. AKI diagnosis is traditionally dependent on changes in serumcreatinine (SCr), a marker with limitations involving time, body habitus, sex,age, steady-state measurement, and patient condition. Primarily due to the lagin the rise of SCr, the diagnosis of AKI is often delayed, which creates asignificant barrier to effective early intervention. 9Treatment for acute myocardial infarction (MI) was transformed bythe use of troponin I measurements in patients with signs and symptoms of acardiac angina. Sensitivity and specificity of troponin elevations andelectrocardiographic changes for MI have allowed practitioners to instituteearly and life-saving therapy. However, whereas the novel AKI biomarkersrecently discovered may serve well as a renal troponin equivalent, AKI lacks animportant parallel to MI.

Simply put, AKI does not hurt.  In order to optimize the utility of AKIbiomarkers, screening systems are needed to identify patients who are at highrisk of developing AKI.9Goldstein SL recently proposed the empiric clinical model of renalangina to identify which critically ill patients would be at the greatest riskof AKI.

Using patient demographic factors and early signs of injury, renalangina is aimed to delineate patients at risk for subsequent severe AKI (AKIbeyond the period of functional injury) versus those at low risk. 10 In thisstudy, the concept of renal angina to improve prediction of subsequent severeAKI has been validated in Indian children admitted in PICU. Material AndMethods: Subjects: All children between 1 months-18 years age group admitted in PICUDuration: one year. Setting: PediatricIntensive Care Unit (PICU) of a tertiary care hospital in Ludhiana District,Punjab. Design: Prospectiveobservational studyInclusion Criteria: All critically ill children between 1 months to 18 years of age admittedto PICU were included in the study.Exclusion criteria: Children with previously known kidney disease and children with hospitalstay less than 72 hours were be excluded.The study was approved by the Institutional Ethics committee.Written consent was obtained from the attendants of thechildren.

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Data Collection: Day 0 was consideredfirst day of PICU admission. Day 3 consisted of the time period between 72 and96 hours after PICU admission. Baseline data at admission included demographicinformation including age, sex, primary diagnosis, system involved, PediatricRisk of Mortality (PRISM-II) scores 11 within 24 hours of hospital admission,renal dysfunction using KDIGO (Kidney Disease Improving Global Outcomes)staging 12, and baseline serum creatinine measurement (SCr). Calculation of Renal angina index (RAI):The index calculation for the fulfilment of renal angina is assessed 8-12 hafter a patient is admitted to an intensive care unit and used for predictionof severe acute kidney injury 72 hours (3 days) later. Risk factors aredetermined as shown and assigned a point value (1, 3, and 5, where 1 denotesthe lowest risk and 5 denotes the highest risk). Mechanical ventilation andvasoactive support should be used within the 12-h timepoint but are notrequired to be simultaneous for a patient to be scored 5 points.

Injury strata was assignedas depicted to a patient as appropriate.  Percentage fluid overload (FO %) wascalculated by {Fluid in(ml)-fluid out (ml) ÷ Patient Weight (gm)} x 100). GFRwas based on estimated creatinineclearance (eCrCl) calculated by the Schwartz equation 13, for determinationof the RAI. Calculation of RenalAngina Index (Range 1 to 40) is a multiplication of the risk and injury scoresassigned (Risk score x FO% score OR Risk score x GFR score), whichever is worseof the two is chosen. The index RAI ?8 was considered fulfillment of renalangina 14.

Fulfillment or the absence of renal angina was denoted ‘RApositive’ or ‘RA negative’.    Outcomes: The primary outcome was the presence of severe AKI on Day3 (Day3-AKI). Severe AKI was defined by the KidneyDisease Improving Global Outcomes (KDIGO) AKI classification stage ?2: serumcreatinine of 200% baseline (a decrease in eCrCl of ?50% from baseline) (26). Day3 was chosen since most PICU patientsdevelop AKI within this timeframe and is a clinically relevant time frame forAKI management. Secondary outcomesincluded use of renal replacement therapy (RRT), need and duration ofmechanical ventilation, length of PICU stay (LOS), and incidence of mortality.

Statistical AnalysesAll statistical analyses wereperformed using STATA version 12 (StataCorp, CollegeStation, TX), SAS version 9.3 (SAS Institute, Cary, NC), and R version 2.14.1(R Development Core Team, Vienna, Austria). An a prioristudy sample size of 5250 patients was expected. The continuous data were summarized usingdescriptive statistics (mean ± standard deviation).

Statistical differencesbetween the mean values were compared using Student’s t-test. A differencebetween the two values was considered to be significant if the P < 0.05. Categoricalvariables were summarized using frequency and proportion and compared bychi-squared or Fisher's exact tests.

An RAI cut-off of ?8 was used to definerenal angina fulfillment ANG(+) and this cut-off was used for operativecharacteristics (20). Simple and multivariablelogistic models were used to predict day 3 AKI using RAI. Area under the curve(AUC) values were calculated for the prediction model (RAI) and compared usingDeLong’s method (27). In all analyses, a P value<0.05 was considered statistically significant.Results: Of the total ____________ patients admittedduring the one year period, 413 (    %)patients wereenrolled for study.

Number______ could not enrolled for differentreasons CKD (n=   ), age less than 2months (n=______), hospital stay less than 72 hours(n=_______). Approximately one third ofpatients i.e. 69/413(16.7 %) were RA + on day day 0 of PICU admission. Meanage in RA +ve group was 5.

92 ± 5.30 yearsas compared to RA -ve group 5.88 ± 5.32 years. Age, gender, admittingdiagnosis or primary system did not affect RA positivity. Sepsis was thediagnosis in 21 % cases and did not affect RA status.

Patients in RA+ve group had higher mean PRISM-IIscores (18.62 ± 6.49) compared to RA -ve group (12.74 ± 6.

49) (p value < 0.001). Additionally,patients in RA+ grouphad longer duration of mechanical ventilation (mean 4.94 ± 4.10 days vs mean 1.

08 ± 2.68 days) (pvalue < 0.001), PICU stay (mean  7.19 ± 5.13 days vs mean  4.72 ± 2.

71) (p value < 0.001), need fordialysis ( 23.2 % vs 0.6% %, p value < 0.001)  and higher mortality( 31.

09 % vs 2 % , p value < 0.001).Predictionof subsequent, severe AKI by Renal Angina Index on admission.  Of thetotal 413 patients enrolled, 33 patients developed Day3-AKI (8%).

  Theincidence of Day 3 AKI was significantly higher in patients with RAI ?8 (RA +group) 25 of 69 (36.2 %) versus 8 of 344 (2.3 %); P= <0.001.

Day 0 RAI positivity(RAI > 8) predicted Day-3 AKI with anAUC of 0.883 95% confidence interval (CI) = 0.823-0.943. RAI > 8positivity had ahigh negative predictive value (NPV)of 97.

67% % (95% CI = 95.84-98.7%), with sensitivity and specificity of  75% and 88.42 % , respectively, and positivepredictive value (PPV) of 35.29% (95% CI = 27.92-43.44 %). RAIprediction by GFR criteria and Fluid overload (FO %) criteriaThepredictive value of  RAI was broken down by composite factorsof kidney injury.

The predictive value for Day-3 AKI by GFR score alone by AUC values was consistentlysuperior when compared tofluid overload score (FO %) AUC 0.877 (95% CI = 0.817-0.936) vs0.774 (95% CI = 0.

685- 0.864).The AUC forRAI for Day-3 AKI improved whenRAI incorporated worse of the two scores (GFR score/FO score). (AUC0.883(95% CI= 0.823-0.943).

  RAIversus KDIGO stage and PRISM score Prediction of RA for Day-3 AKI was superior to KDIGOstage 1 injury at admission;fulfillment of renal angina demonstrated higher sensitivity (27.27%), PPV of 25%, NPV of 93.63%and a higherYouden’s index ( ____________) than KDIGO stage 1,although specificity was found to be higher with KDIGO stage 1 (92.89%). Similar results were seen when RA was compared to KDIGO stages 2–3 (Youden’s index=_____). When compared directly, RAI outperformed PRISM-II for theprediction of day 3 AKI. (AUC=0.

764)(95% confidence interval (CI) = 0.672-0.856).Discussion:  Renal angina index was developed by Goldstein to identify criticallyill patients at greatest risk of AKI.10  In the current study, we operationalize renalangina index in a tertiary care hospital of a developing country and show thatrenal angina index improves prediction of subsequent severe AKI and alsooutperforms currently used clinical thresholds for early signs of kidneyinjury, or severity of illness scores.

RAI was derived as a composite of risk factors and clinicalsigns of AKI. The logic behind the equation dictates that as a patient achieveshigher risk they require less “clinical sign of AKI” early on to fulfill renalangina. Similarly, if a patient has less risk but shows more overt signs of clinicalAKI signs, renal angina would also be fulfilled.15 RAI derivation was based on available AKI epidemiologyreported in select pediatric populations: children admitted to the ICU carryincreased risk over the general population (4.5–10%),16,17 children receiving bone marrowtransplantation have ~3× risk (11–21%)18, and those who are intubated and on vasopressor supportcarry nearly 5× risk versus the general ICU population (51%). 3 The ‘signs of injury’ (i.e.

,kidney pain) in the RAI include GFR and fluid overload.Troponin measured in patientswho exhibit cardiac angina, a combination of clinical signs and known coronarydisease risk factors, allows practitioners to rule in myocardial infarction. Inthis select, risk-stratified population, troponin has great specificity andPPV. When measured in patients without cardiac angina, troponin losesperformance.

Unfortunately, unlike a heart attack, AKI does not carry an easilyidentifiable physical prodrome such as cardiac angina. Simply put, a kidneyattack does not ‘hurt’. So clinicians tried to find a novel renal equivalent of”cardiac angina” so that a suitable biomarker can be applied to select patientshaving high risk of AKI.Renal angina fulfillment identifies children at the highestrisk of suffering subsequent severe AKI. For a clinician, the ability topredict the presence of severe AKI 3 days in advance carries obvious benefit. Fluids are the second mostcommon intervention in acutely ill patients (after oxygen). The benefits ofearly fluid resuscitation in patients with shock and acute kidney injury (AKI)are already accepted. There is evidence that fluid administration beyond thecorrection of hypovolaemia is associated with increased morbidity, a longerhospital stay and mortality.

In a recent article in Critical Care, Wang et al.analysed the data of 2526 patients admitted to 30 intensive care units (ICUs)in China and showed that even relatively small degrees of fluid overload wereindependently associated with an increased risk of AKI and mortality 19.In the RajitBasu etal study,based on the most optimal Youden’s index (0.49) and highest negative predictivevalue (to safely rule out development of subsequent AKI), an RAI > 8 wastaken as cutoff to label Renal Angina positivity.15 Only day 3 AKI was chosen to define outcome as most PICUpatients develop AKI within this time frame and it surpasses the time frame offunctional AKI (prerenal AKI). Also, time frame of 8 h was kept to assess fluidoverload as it was beyond the generally accepted window of ‘early goal-directedtherapy’ (EGDT) of resuscitation.

20    In our study atotal of 413 patients were included. Day 0 Renal Angina positive was seen in16.7% patients. Of  renal angina positivepatients 36.

2 %  developed subsequentsevere AKI compared to 2.3 % of the other group, which was highly significant(p<0.001). Performance of the test was also calculated. Sensitivity came tobe 75%.

Specificity came to be 88.42%. Positive predictive value was low(35.

29%) whereas a high negative predictive value of 97.67% was present. AUCfor the same came to be 0.877.

When the RAI was derived basedon either GFR score or Fluid overload alone, it was still able to predict Day-3AKI. Although FO score did not perform as well as GFR score, FO score wassimilar to PRISM-II scores for prediction of Day-3 AKI. More importantly, theprediction for Day-3 AKI improved when the worse value of FO or GFR score wasused compared to using  GFR score alone.Also, Renal angina outperformed early signs of injury i.e. KDIGO stages I. Ourresults were similar to those seen in the Rajit Basu et al. study.

15Several AKI biomarkers havedemonstrated promising results for the identification and prediction of AKI inchildren.21 Identifying patients at risk for severe and long-lasting AKI in the PICU iscrucial as risk stratification could allow more judicious AKI biomarkerassessment to drive therapeutic intervention, thereby increasing theirpredictive performance and cost-effectiveness. 22Limitation of the study was thatbaseline creatinine was calculated from admission serum creatinine and patientheight using the Schwartz correction. This was done, as most patients did nothave their lowest creatinine value (up to 3 months before PICU admission) toestablish a reference value. In our study, to define severe subsequent AKI,estimated creatinine clearance criteria of KDIGO (SCr of 200% baseline or  decrease in eCCl of ?50% from baseline) wastake to define primary outcome and urine output criteria was not taken.

  Thus, renal angina index couldbe used as a simple and important bedside tool without the need of anyexpensive equipment to detect patients at risk of severe AKI. This can allow usto use novel AKI biomarker or therapy trial, which could ultimately guidetreatment strategy in critically ill children.