METHVEN S, MACGREGOR MS, TRAYNOR JP, O'REILLY DS, DEIGHAN CJ NEPHROL DIAL TRANSPLANT, SEPT 2010 Assessing proteinuria in chronic kidney disease: protein–creatinine ratio versus albumin–creatinine ratio SPEAKER : Dr. RAHUL CHAUDHARY SENIOR RESIDENT : Dr. ANURAG

Introduction Identification and quantification of proteinuria are core elements in the diagnosis and management of CKD Proteinuria is associated with  an increased risk of progressive kidney failure  cardiovascular disease and death  monitor the progress of kidney disease  to assess response to therapy Timed urine collections (usually performed over 24 h) are considered the gold standard

Urine formation

Urine proteins TOTAL PROTEIN = 150 – 200mg/day ; ALBUMIN <30mg/day

How to assess the amount of protein in urine? 24 – hour urine collection Poor compliance ; difficult in OPD set up Random urine protein/albumin concentration Variation in urine protein excretion (water intake,rate of diuresis,exercise,diet….) Urine protein creatinine ratio Protein and creatinine excretion rates are fairly constant throughout the day as long as the GFR remains constant

Introduction CONCLUSION :The protein : creatinine ratio on a random urine specimen provides evidence to “rule out” the presence of significant proteinuria as defined by a 24-h urine excretion measurement.

Guideline recommendations Guideline Recommendation KDOQI ( Kidney disease outcome quality initiative) Monitor proteinuria using ACR unless ACR exceeds mg/g, when TPCR is acceptable NICE (National institute for health and clinical excellence) ACR for urine analysis CARI ( Caring for Australasians with renal impairment) TPCR in patients with non-diabetic kidney disease ACR for diabetic patients

Aim of the study Examine the relationship between TPCR, ACR and 24-hr urinary protein Compare the diagnostic performance of TPCR and ACR at various thresholds To decide which is the optimal test to identify significant proteinuria

Materials and methods Single centre study  Kilmarnock, UK Retrospective analysis Perusal of records in the electronic patient record Laboratory assays  Random spot urine samples sent for all patients attending the renal clinic  24 hr urine evaluation done only on request AnalyserUrine albuminUrinary protein Prior to Aug 2006Bayer Advia 1650Immunoturbidimetry using anti-human albumin antiserum Pyrogallol red calorimetric method After Aug 2006Abbott Architect 2000 Immunoturbidimetry using anti-human albumin antiserum Turbidimetric method using benzethonium No significant difference in the precision and accuracy of two methods

Method of patient selection Searched for patients with TPCR and ACR measured on the same date 7830 patients were identified with simultaneous ACR and TPCR results Exclusions :  489 samples were analysed prior to 29 November 1999 and laboratory assay details were unavailable  88 children <18 years old excluded  411 patients receiving renal replacement therapy

Data acquisition Following details were recorded  Gender  Age at the time of urine collection  Primary renal disease  Use of ACE-I / ARB  Weight / height / Blood pressure  Serum creatinine  eGFR using the 4 variable MDRD equation Correlation was assessed using spearman’s rho Bland-Altman analysis was used to compare different measures of proteinuria Receiver operator curve were constructed to allow comparison of assays for key threshold values of proteinuria ACE-I – angi0tensin converting enzyme inhibitors;ARB –angiotensin receptor blockers;eGFR – estimated Glomerular filtration rate;MDRD – modification of diet in renal disease

Baseline characteristics

Relationship between ACR and TPCR Relationship was non-linear ACR is always less than TPCR (as expected)

TPCR, ACR and 24h urine protein  Results were available for 1696 patients  TPCR is more highly correlated with 24hr urine protein  In the range mg/day where clinical decisions are made, there is greater scatter with ACR

Ability of TPCR or ACR for prediction TPCR is more sensitive than ACR but less specific 24hr urine protein used as a gold standard

ROC curve analysis

Discussion LIMITATIONS Retrospective study Relationship demonstrated may only apply to the assay used in this study STRENGTH Large number of patients Representative nature of unselected adult population attending a general nephrology clinic.

Discussion TPCR is a highly sensitive and reasonable specific test for detection of significant proteinuria ie it can be used to rule out the presence of proteinuria and in those patients who have a positive result a full 24 hour collection and quantification is indicated. ACR performs significantly less well by ROC curve analysis Since these are screening tests, hence sensitivity is more important Total proteinuria cannot be predicted from albuminuria because of the variable proportion of non albumin proteins The diagnostic performances of both tests vary with age, gender, and to some extent eGFR, an effect that is related to muscle mass – hence clinician should interpret the result with the patient’s muscle mass in mind rather than rigidly sticking to a single cut off point.

Discussion Both ratios have their own limitations ─ TPCR and ACR may underestimate 24hour protein excretion ─ Analysis must be immediately done in a fresh sample ─ Urine creatinine measurement is another source of error ─ Urine creatinine is variable and hence the ratio is variable.

Figure 26.8 The Renal Corpuscle Figure 26.8a, b

Interpretation of Urine Albumin to Creatinine Ratio  Normal Ratio (in general <30 mg/g is normal)  Men: < (or 17 mg albumin to 1 gramCreatinine)Creatinine  Women: <0.025 (or 25 mg albumin to 1 gram Creatinine)Creatinine  Microalbuminuria: mg albumin/g CreatinineCreatinine  Macroalbuminuria: >300 mg albumin/g CreatinineCreatinine

Comparison of different measures of urinary protein excretion for prediction of renal events. Heerspink HJ, et al. J Am Soc Nephrol 21: 1355–1360,2010 Heerspink et al (2010) did a study on 701 participants of the Reduction In Endpoints in Non insulin Dependent Diabetes Mellitus with the Angiotensin-II Antagonist Losartan (RENAAL) trial Four standard methods for measuring urine protein compared:  24-hour urine protein excretion  24-hour urine albumin excretion  First morning void spot urine albumin conc  First morning void spot urine albumin-to-creatinine ratio (ACR)

Study addressed which of the four methods most strongly associates with the clinical outcome of renal progression, defined by a doubling of serum creatinine or the development of ESRD All four methods were strongly associated with renal progression Associations for Spot urine ACR were modestly stronger than those for the Other urine protein measurements and the superiority of urine ACR was consistent across subgroups defined by gender, race,and age