Using Albumin:Creatinine Ratio (ACR) for Nephrology Referral in Primary Care Sohan Shah

Background Renal conditions are becoming increasingly prevalent in the community. Proteinuria screening is unanimously used as a diagnostic and prognostic marker. Primary care physicians need to know who to refer, when and how. Dip-stick urinalysis has been widely condemned as a screening tool. 24-hour protein collection, despite being the gold- standard, has its own problems. A ‘middle ground’ screening test needed establishing.

Background Spot-urine tests (SpUr) such as albumin:creatinine ratio (ACR) and protein:creatinine ratio (PCR) are now available. Several advantages: – Creatinine compensates for urine flow – Quick & Cheap – Predict outcomes (mortality and morbidity)

What do Renal Guidelines say? GuidelineProtein Detection Method Definition of Proteinuria (non- Diabetic patients) Referral Criteria NKF-KDOQI (2002)ACR preferred for all patients. ACR >30 mg/mmol PCR >20 mg/mmol KHA-CARI (2013)ACR preferred for all patients. ACR ≥30 mg/mmol PCR ≥50 mg/mmol ACR* ≥ 30 mg/mmol, PCR* ≥ 50 mg/mmol KDIGO (2013)ACR preferred for all patients. ACR ≥30 mg/mmol PCR ≥50 mg/mmol ACR* ≥ 30 mg/mmol, PCR* ≥ 50 mg/mmol SIGN (2008) PCR preferred for all non-diabetic patients. ACR preferred for diabetic patients. PCR >100 mg/mmol ACR >30 mg/mmol NICE (2008)ACR preferred for all patients. ACR ≥30 mg/mmol PCR ≥50 mg/mmol ACR >70 mg/mmol PCR >100 mg/mmol The above data applies to adult patients only. In all cases, first-void morning samples are preferred. *Persistent significant proteinuria results required.

Methods Urine samples from 2006 onwards analysed. Samples with concurrent data for 24h UP, ACR and PCR used within the study. All laboratory techniques and assays used are well recognised and widely used for the detection and quantification of albumin, protein and creatinine.

Results 211,249 urine samples analysed from had concurrent data for ACR, PCR and 24h UPC. One sample excluded for anomalous results. 502 samples analysed. 211,249 Samples 503 With Relevant Data 502 Post- Exclusion

ACR vs 24h UP ACR performs reasonably well: – Spearman’s Rho = (p < 0.001) – R 2 = Over 1g/day, correlation is less strong.

PCR vs 24h UP PCR performs even better comparatively: – Spearman’s Rho = (p < 0.001) – R 2 = Correlation remains strong at low and high thresholds.

ACR vs PCR ACR and PCR correlate well with each other: – Spearman’s Rho = (p < 0.001) – R 2 = Indicative of many outliers – At extremely high and low levels of PCR, correlation is very poor. Explained by variable proportion of non-albumin proteins.

ACR vs PCR As such, the association between ACR and PCR is non-linear. – Logarithmic scale shown with linear regression line.

ROC Analysis ROC curve shows the ability of SpUR to correctly identify patients with or without significant proteinuria. Compares SpUr to 24 UPC. Key measurement is the area under the curve (AUC): – AUC of 1 (100%) represents a perfect test. – AUC of 0.5 (50%) represents a useless test.

ROC - ACR 481 samples analysed (non-exact values excluded). Optimal ACR cut-off is 27.11mg/mmol (95% CI ) Estimate (%)95% Confidence Interval ROC Area95.3(93.1, 97.5) Sensitivity90.7(84.3, 95.1) Specificity89.5(86.0, 92.5) PPV75.0(67.4, 81.6) NPV96.5(94.0, 98.2)

ROC - PCR 480 samples analysed (non-exact values excluded). Optimal PCR cut-off is 69.55mg/mmol (95% CI ) Estimate (%)95% Confidence Interval ROC Area97.8(96.6, 98.9) Sensitivity96.1(91.2, 98.7) Specificity90.9(87.5, 93.6) PPV78.5(71.2, 84.6) NPV98.5(96.6, 99.5)

Summary of ROC Analysis SensitivitySpecificityPPVNPV ACR ≥ ACR ≥ ACR ≥ ACR ≥ ACR ≥ PCR ≥ PCR ≥ PCR ≥

Cost Analysis In 2008, NICE costing analysis showed that on average, PCR was £0.74 cheaper per sample. – Av. ACR = £2.16 – Av. PCR = £1.42 – Av. Urinalysis = £0.21 In our study, – Av. ACR = £0.76 – Av. PCR = £0.60 Implications on a national scale within NHS.

Conclusion SpUr ACR and PCR are suitable screening tests for significant proteinuria. – Unselected cohort – No time analysis – Representative of a 1° care population We recommend use of a lower cut-off value for increased sensitivity: – ACR >45, PCR >70

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